Method for production of 3-hydroxypropan-1-one compound, method for production of 2-propen-1-one compound and method for production of isoxazoline compound

ABSTRACT

There is provided a novel intermediate for producing pesticides. A method for producing the compound of Formula (3) comprises reacting an aromatic ketone compound of Formula (4) and a substituted acetophenone compound of Formula (5) as starting raw materials in an organic solvent or water in the presence or absence of an additive in the presence of a base in a suspended state. A method may comprise dehydrating the compound of Formula (3). A method for producing compound (2) in one step comprises reacting compound (4) and compound (5) to obtain compound (3). Further, a method for producing an isoxazoline compound of Formula (1) comprises reacting compound (2) and a hydroxylamine in an aliphatic or an aromatic hydrocarbon solvent which is optionally substituted by a halogen atom by adding an additive selected from a phase-transfer catalyst, a C 1 -C 6  alcohol and an aprotic polar solvent in the presence of a base and water.

This is a Division of application Ser. No. 14/584,642 filed on Dec. 29,2014, which in turn is a Division of application Ser. No. 12/452,347filed Dec. 28, 2009, which in turn is a National Phase application ofPCT/JP2008/061771 filed on Jun. 27, 2008. The disclosures of the priorapplications are hereby incorporated by reference herein in theirentirety.

TECHNICAL FIELD

The present invention relates to a method for producing a3-hydroxypropan-1-one compound, a 2-propen-1-one compound and anisoxazoline compound which are useful for functional materials such asmedical drugs, agricultural chemicals or electronic materials orproduction intermediates thereof.

BACKGROUND ART

Methods for producing an isoxazoline compound from a 1,3-bis(substitutedphenyl)-3-substituted-2-propen-1-one compound and hydroxylamine as rawmaterials have been known in, for example, Non-patent Documents 1 to 6.

Several methods for producing a 1,3-bis(substitutedphenyl)-3-substituted-3-hydroxypropan-1-one compound from an aromaticketone compound and a substituted acetophenone compound as starting rawmaterials have been known (for example, Patent Document 1 and Non-patentDocuments 7 to 15).

Moreover, methods for producing a 1,3-bis(substitutedphenyl)-3-substituted-2-propen-1-one compound from a 1,3-bis(substitutedphenyl)-3-substituted-3-hydroxypropan-1-one compound as a raw materialhave been known in, for example, Non-patent Documents 10 and 11.

Furthermore, methods for producing a 1,3-bis(substitutedphenyl)-3-substituted-2-propen-1-one compound from an aromatic ketonecompound and a substituted acetophenone compound as starting rawmaterials in one step have been known in, for example, Non-patentDocuments 18 to 20.

-   [Patent Document 1]-   WO 2007/074789 pamphlet-   [Non-patent Document 1]-   Farmaco, Edizione Scientifica (1971), 591-596-   [Non-patent Document 2]-   Zeitschrift fuer Naturforschung, Teil B: Anorganische Chemie,    Organische Chemie (1977), 443-446-   [Non-patent Document 3]-   Bulletin des Societes Chimiques Beiges (1987), 293-302-   [Non-patent Document 4]-   Journal of Heterocyclic Chemistry (1998), 989-990-   [Non-patent Document 5]-   Synthetic Communication (1999), 3237-3250-   [Non-patent Document 6]-   Archives of Pharmacal Research (2004), 885-892-   [Non-patent Document 7]-   Zhurnal Organicheskoi Khimii, vol. 26, No. 10, 2205-2208 (1990)-   [Non-patent Document 8]-   Journal of Fluorine Chemistry, vol. 113, 105-109 (2002)-   [Non-patent Document 9]-   Organic Letters vol. 7, No. 22, 5103-5105 (2005)-   [Non-patent Document 10]-   Journal of Organic Chemistry, vol. 71, 3822-3828 (2006)-   [Non-patent Document 11]-   Chinese Journal of Chemistry, vol. 23, 584-588 (2005)-   [Non-patent Document 12]-   Synthesis, No. 17, 2901-2905 (2005)-   [Non-patent Document 13]-   Tetrahedron Letters, vol. 38, 8727-8730 (1997)-   [Non-patent Document 14]-   Tetrahedron, vol. 58, 8263-8268 (2002)-   [Non-patent Document 15]-   Organic Process Research and Development, vol. 8, 18-21 (2004)-   [Non-patent Document 16]-   Tetrahedron, Vol. 58, No. 39, 7775-7780 (2002)-   [Non-patent Document 17]-   Tetrahedron Letters, vol. 46, 8913-8915 (2005)-   [Non-patent Document 18]-   Journal of Organic Chemistry, Vol. 71, No. 9, 3545-3555 (2006)-   [Non-patent Document 19]-   Journal of Fluorine Chemistry, Vol. 125 No. 1, 91-94 (2004)-   [Non-patent Document 20]-   Journal of Molecular Catalysis A: Chemical, Vol. 181, 179-187 (2002)

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention

The reaction conditions described in Non-patent Documents 1 to 4 and 6are the reactions in which alcoholic solvents such as ethanol are usedto react basic compounds such as sodium hydroxide, potassium hydroxide,barium hydroxide and pyridine. In recent synthetic examples, methods ofreacting the basic compound in an alcoholic solvent are common methodsused for producing an isoxazoline compound from a 1,3-bis(substitutedphenyl)-3-substituted-2-propen-1-one compound and hydroxylamine as rawmaterials, as far as the present inventors have known. However, yieldsare moderate in many cases of these reaction examples. In addition,although these methods require a liquid separation operation in order toremove overused hydroxylamine, these methods do not provide industrialsatisfaction due to the difficulty in recovery, the increase inenvironmental load and the increase in cost when alcoholic solvents areused. Non-patent Document 5 describes the method of using pyridine as asolvent and a base. However, this method provides low yield of around50%, and pyridine also has difficulty in recovery similar to alcohol.Moreover, Non-patent Document 5 describes the reaction example in whichmethylene chloride is used as a solvent. However, this reaction examplehas limitation of equipment and the like in industrial production,because microwave irradiation is required.

As described above, in related art methods, there is no method ofproducing an isoxazoline compound in low-polarity solvents asrepresented by toluene which are recovered easily from a1,3-bis(substituted phenyl)-3-substituted-2-propen-1-one compound andhydroxylamine as raw materials, so that there is room for improvement.

In the reaction condition described in Non-patent Document 7, sincen-butyl lithium which is expensive and requires careful handling is usedas a base, this reaction is not satisfactory in industrial processes. Inthe reaction condition described in Non-patent Document 8, an aromaticketone compound is required to be converted into imine once and then ismade to react. After the reaction, the imine part is required to bereconverted. Therefore, this reaction leads to an increase in productioncost and waste materials, and is not satisfactory as an industrialproduction method. In the reaction conditions described in Non-patentDocuments 9 to 11, proline is used as a catalyst. The yields in thesedescriptions are comparatively high. However, since solvents which havedifficulty in recovery or halogen-based solvents are required, thereaction is not satisfactory in an industrial production method. In thereaction conditions described in Non-patent Documents 12 and 13, thereaction leads to an increase in production cost and waste materialsbecause titanium tetrachloride is used stoichiometrically, and has aproblem of equipment and the like in industrial production because thereaction requires ultra cold temperature of −78° C. In the reactionconditions described in Non-patent Document 14, the reaction isconducted in water by adding a surfactant. This reaction is required tobe effected after an aromatic ketone compound is converted into a silylether. This leads to an increase in production cost and waste materials,and the reaction is not satisfactory as an industrial production method.In the reaction conditions described in Non-patent Document 15, thereaction is also conducted in water. However, the amount of water to beused is very large, and this reaction is not satisfactory for industrialproduction in volume efficiency.

In the reaction conditions described in Non-patent Document 16, adehydration agent and a base are used in a solvent amount. In thereaction conditions described in Non-patent Document 17, solvents areused in some cases, but the solvents used are halogen-based organicsolvents. These reactions are not satisfactory in industry, because thereactions described in both documents have large environmental loads andincreased costs.

In the reaction conditions described in Non-patent Document 18, one ofthe starting raw materials is converted into a phosphorus ylide, andthis ylide is reacted with another starting raw material. Therefore,this reaction is not satisfactory in production cost. In the reactionconditions described in Non-patent Document 19, raw materials arereacted with each other using a transition metal catalyst. However, thisreaction is difficult to use in industry, because a tin compound whichhas anxiety of toxicity is required to be used. In the reactionconditions described in Non-patent Document 20, a solid catalyst whichcan be recovered and reused is used. However, the reaction is notsatisfactory in industry, because the conversion ratio is low.

As described above, in related art methods, there is no method forproducing a 1,3-bis(substitutedphenyl)-3-substituted-3-hydroxypropan-1-one compound from an aromaticketone compound and a substituted acetophenone compound as raw materialswith water which is harmless for the environment and creatures as asolvent without using expensive reagents and with good volumeefficiency. In addition, a method for production characterized in that areaction is conducted in the presence of a base in a low-polaritysolvent as represented by toluene which is recovered easily and theequilibrium reaction is distributed to the target product side bygenerating slurry has not been known, so that there is room forimprovement.

In addition, there is no method for producing a 1,3-bis(substitutedphenyl)-3-substituted-2-propen-1-one compound from a 1,3-bis(substitutedphenyl)-3-substituted-3-hydroxypropan-1-one compound as a raw materialin a low-polarity solvent as represented by toluene which is recoveredeasily by using a dehydration agent and a base, and a method forproducing a 1,3-bis(substituted phenyl)-3-substituted-2-propen-1-onecompound from an aromatic ketone compound and a substituted acetophenonecompound as starting raw materials in one step has also not been known,so that there is room for improvement.

Means for Solving the Problems

As a result of an intensive investigation for achieving theabove-described objects, the present inventors have discovered a methodfor producing a 1,3-bis(substitutedphenyl)-3-substituted-3-hydroxypropan-1-one compound from an aromaticketone compound and a substituted acetophenone compound as raw materialsby conducting the reaction in the presence of a base in water which isharmless or in a low-polarity solvent as represented by toluene which isrecovered easily and distributing the equilibrium reaction to the targetproduct side by generating slurry, and have accomplished the presentinvention.

In addition, the present inventors also have discovered a method forproducing a 1,3-bis(substituted phenyl)-3-substituted-2-propen-1-onecompound from a 1,3-bis(substitutedphenyl)-3-substituted-3-hydroxypropan-1-one compound as a raw materialin a low-polarity solvent as represented by toluene which is recoveredeasily by using a dehydration agent and a base, and moreover a methodfor producing a 1,3-bis(substituted phenyl)-3-substituted-2-propen-1-onecompound from an aromatic ketone compound and a substituted acetophenonecompound as starting raw materials in one step, and have accomplishedthe present invention.

Furthermore, the present inventors also have discovered a method forproducing an isoxazoline compound from 1,3-bis(substitutedphenyl)-3-substituted-2-propen-1-one compound and hydroxylamine as rawmaterials in low-polarity solvents as represented by toluene which arerecovered easily, and have accomplished the present invention.

Namely, the present invention is:

[1] a method for producing an isoxazoline compound represented byFormula (1):

(where R¹, R², X, A¹, A², A³, A⁴, A⁵, A⁶ and A⁷ represent the samemeaning as described below), includes reacting a 1,3-bis(substitutedphenyl)-3-substituted-2-propen-1-one compound represented by Formula(2):

(where R¹ represents a C₁-C₆ haloalkyl or C₃-C₈ halocycloalkyl;

each of A¹, A², A³ and A⁴ independently represents N or C—Y;

each of A⁵, A⁶ and A⁷ independently represents N or C—X;

X represents a hydrogen atom, a halogen atom, cyano, nitro, —SF₅, C₁-C₆alkyl, C₁-C₆ haloalkyl, hydroxy (C₁-C₆) haloalkyl, C₁-C₆ alkoxy (C₁-C₆)haloalkyl, C₁-C₆ haloalkoxy (C₁-C₆) haloalkyl, C₃-C₈ halocycloalkyl,—OR³, —OSO₂R³ or —S(O)_(r)R³; and each X may be the same as or differentfrom each other;

R³ represents a C₁-C₆ alkyl, C₁-C₄ alkoxy (C₁-C₄) alkyl, C₁-C₆ haloalkylor C₁-C₃ haloalkoxy (C₁-C₃) haloalkyl;

R² represents a C₁-C₆ alkyl, a halogen atom, cyano, nitro, —NH₂,—N(R⁵)R⁴, —OH, —OR³, benzyloxy, —OSO₂R³, phenylsulfonyloxy,phenylsulfonyloxy substituted by (Z)_(p1), —C(O)OH, —C(O)OR³, —C(O)NH₂,—C(O)N(R^(1b))R^(1a), —C(S)N(R^(1b))R^(1a), -L-Q, -L-N(R^(1c))R^(1d),—S(O)_(r)-L²-Q² and a substituent selected from D-1 to D-50;

Y represents a hydrogen atom, a halogen atom, cyano, nitro, C₁-C₄ alkyl,C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₁-C₆ alkylthio, C₁-C₆haloalkylthio, C₁-C₆ alkylsulfonyl, C₁-C₆ haloalkylsulfonyl, —NH₂, or—N(R⁵)R⁴, and each Y may be the same as or different from each other;

two adjacent Ys may form A⁸=A⁹−A¹⁰=A¹¹ together;

each of A⁸, A⁹, A¹⁰ and A¹¹ independently represents N or C—Y¹;

Y¹ represents a hydrogen atom, a halogen atom, cyano, nitro, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₁-C₆ alkylthio,C₁-C₆ haloalkylthio, C₁-C₆ alkylsulfonyl, C₁-C₆ haloalkylsulfonyl, —NH₂,or —N(R⁵)R⁴, and each Y¹ may be the same as or different from eachother;

R⁴ represents a C₁-C₆ alkyl, —CHO, C₁-C₆ alkylcarbonyl, C₁-C₆haloalkylcarbonyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkylthiocarbonyl, C₁-C₆alkoxythiocarbonyl, C₁-C₆ alkyldithiocarbonyl, C₁-C₆ alkylsulfonyl orC₁-C₆ haloalkylsulfonyl;

R⁵ represents a hydrogen atom or C₁-C₆ alkyl;

R^(1a) represents a C₁-C₆ alkyl, C₁-C₆ alkyl optionally substituted byR⁸, C₃-C₆ cycloalkyl which may be ring-condensed by benzene ring, C₃-C₆alkenyl, C₃-C₆ haloalkenyl, C₃-C₆ alkynyl, —N(R¹¹)R¹⁰, —C(O)OR⁹,—C(O)NH₂, —C(O)NHR⁹, —C(R⁷)═NOR⁶, phenyl, phenyl substituted by(Z)_(p1), D-5, D-7, D-10, D-11, D-12, D-14, D-15, D-18, D-31, D-32,D-42, D-43, D-45, D-46, D-48, E-1, E-2, E-3, E-4 or E-7;

R^(1b) represents a hydrogen atom, C₁-C₆ alkyl, C₁-C₄ alkoxy (C₁-C₄)alkyl, cyano (C₁-C₆) alkyl, C₃-C₆ alkynyl, —C(O)R⁹ or —C(O)OR⁹,

or represents that R^(1b) may form a 3-7 membered ring with a nitrogenatom to be bonded, by forming a C₂-C₆ alkylene chain together withR^(1a), and this alkylene chain may contain one oxygen atom, sulfur atomor nitrogen atom in this case;

L represents —C(R^(2a))(R^(2b))—, —C(R^(2a))(R^(2b))CH₂—,—CH₂C(R^(2a))(R^(2b))— or —N(R^(2c))—;

Q represents a hydrogen atom, a halogen atom, cyano or nitro;

R^(1c) represents a hydrogen atom, —C(O)R^(3a), —C(O)OR^(3a),—C(O)SR^(3a), —C(O)N(R^(3b))R^(3a), —C(S)N(R^(3b))R^(3a) or—S(O)₂R^(3a);

R^(1d) represents a hydrogen atom, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₄alkoxy (C₁-C₄) alkyl, C₁-C₄ haloalkoxy (C₁-C₄) alkyl, C₁-C₄ alkylthio(C₁-C₄) alkyl, C₁-C₄ alkylsulfonyl (C₁-C₄) alkyl, cyano (C₁-C₆) alkyl,C₃-C₆ cycloalkyl, C₃-C₆ cycloalkyl (C₁-C₄) alkyl, C₃-C₆ alkenyl, C₃-C₆alkynyl, —C(O)R^(3c), —C(O)OR^(3c), —C(O)SR^(3c), C₁-C₆ haloalkylthio orC₁-C₆ alkylsulfonyl,

or represents that R^(1c) may form a 5-7 membered ring with a nitrogenatom to be bonded, by forming a C₄-C₆ alkylene chain together withR^(1d), and this alkylene chain may contain one oxygen atom, sulfur atomor nitrogen atom in this case and may be optionally substituted by aC₁-C₆ alkyl group, —CHO group, C₁-C₆ alkylcarbonyl group, C₁-C₆haloalkylcarbonyl group, C₁-C₆ alkoxycarbonyl group, C₁-C₆haloalkoxycarbonyl group, C₁-C₆ alkylaminocarbonyl group, C₁-C₆haloalkylaminocarbonyl group, oxo group or thioxo group;

R^(2a) represents a hydrogen atom, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxycarbonyl, —C(O)NH₂ or —C(S)NH₂;

R^(2b) represents a hydrogen atom or C₁-C₆ alkyl, or represents thatR^(2b) may form a 3-6 membered ring with a carbon atom to be bonded, byforming a C₂-C₅ alkylene chain together with R^(2a), and this alkylenechain may contain one to three oxygen atom(s), sulfur atom(s) ornitrogen atom(s) in this case;

R^(2c) represents a hydrogen atom, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkylcarbonyl, C₁-C₆ haloalkylcarbonyl or C₁-C₆ alkoxycarbonyl;

R^(3a) represents a C₁-C₆ alkyl, C₁-C₆ haloalkyl, (C₁-C₄) alkyloptionally substituted by R^(4a), C₃-C₆ cycloalkyl, C₃-C₆halocycloalkyl, E-1, E-2, E-4, C₂-C₆ alkenyl, C₂-C₆ haloalkenyl, C₂-C₆alkynyl, phenyl, phenyl substituted by (V)_(p1), D-3, D-4, D-12 to D-14,D-42 or D-43;

R^(3b) represents a hydrogen atom or C₁-C₆ alkyl;

R^(3c) represents a hydrogen atom, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₃-C₆cycloalkyl (C₁-C₄) alkyl, C₃-C₆ cycloalkyl, C₃-C₆ alkenyl or C₃-C₆alkynyl, or represents that R^(3c) may form a 5-7 membered ring with anitrogen atom, carbon atom, oxygen atom or sulfur atom to be bonded, byforming an ethylene chain or benzene ring bonded at an ortho-positiontogether with R^(3a);

R^(4a) represents a halogen atom, cyano, nitro, C₃-C₆ cycloalkyl, C₁-C₄alkoxy, C₁-C₆ alkoxycarbonyl, S(O)_(r)R^(5a), D-42 or D-43;

R^(5a) represents a C₁-C₄ alkyl;

V represents a halogen atom, cyano, nitro, C₁-C₆ alkyl, C₁-C₆ haloalkyl,—OH, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ alkylsulfonyloxy, C₁-C₆haloalkylsulfonyloxy, C₁-C₆ alkylthio, C₁-C₆ haloalkylthio, C₁-C₆alkylsulfinyl, C₁-C₆ haloalkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆haloalkylsulfonyl, —NH₂, C₁-C₆ alkylamino, di(C₁-C₆ alkyl) amino, C₁-C₆alkoxycarbonyl, —C(O)NH₂, C₁-C₆ alkylaminocarbonyl, C₁-C₆haloalkylaminocarbonyl, di(C₁-C₆ alkyl) aminocarbonyl, —C(S)NH₂,—S(O)₂NH₂, C₁-C₆ alkylaminosulfonyl or di(C₁-C₆ alkyl) aminosulfonyl,and each V may be the same as or different from each other when p1represents an integer of 2 or more;

moreover, when two Vs are adjacent, the two adjacent Vs may form a5-membered ring or a 6-membered ring with carbon atoms bonding to eachof the two Vs by forming —OCH₂O— or —OCH₂CH₂O—, and hydrogen atomsbonding to each carbon atom forming the ring may be optionallysubstituted by halogen atoms in this case;

R⁶ represents a C₁-C₆ alkyl or C₁-C₆ haloalkyl;

R⁷ represents a hydrogen atom or C₁-C₆ alkyl;

R⁸ represents a halogen atom, cyano, amino, C₃-C₆ cycloalkyl, C₃-C₆halocycloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ alkylthio, C₁-C₆haloalkylthio, C₁-C₆ alkylsulfinyl, C₁-C₆ haloalkylsulfinyl, C₁-C₆alkylsulfonyl, C₁-C₆ haloalkylsulfonyl, —C(O)R¹⁴, —C(O)OR¹⁴, —C(O)NH₂,—C(O)N(R¹⁵)R¹⁴, —C(S)NH₂, —C(S)N(R¹⁵)R¹⁴, —C(R⁷)═NOH, —C(R⁷)═NOR⁶,phenyl, phenyl substituted by (Z)_(p1), D-1 to D-50 or E-1 to E-8;

D-1 to D-50 represent aromatic heterocyclic rings represented by thefollowing structural formulae:

Z represents a halogen atom, cyano, nitro, amino, C₁-C₆ alkyl, (C₁-C₆)alkyl optionally substituted by R¹⁶, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, C₁-C₆ alkylthio, C₁-C₆ haloalkylthio, C₁-C₆alkylsulfinyl, C₁-C₆ haloalkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆haloalkylsulfonyl, C₁-C₆ alkoxycarbonyl, —C(O)NH₂, —C(S)NH₂, —S(O)₂NH₂,—C(O)N(R¹⁸)R¹⁷, —C(S)N(R¹⁸)R¹⁷, C₁-C₆ alkylaminosulfonyl or di(C₁-C₆alkyl) aminosulfonyl, and each Z may be the same as or different fromeach other when p1, p2, p3 or p4 represents an integer of 2 or more;

E-1 to E-8 represent saturated heterocycles represented by the followingstructural formulae:

R⁹ represents a C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy (C₁-C₄)alkyl, C₁-C₆ alkylthio (C₁-C₄) alkyl, C₃-C₈ cycloalkyl, C₃-C₆ alkenyl orC₃-C₆ alkynyl;

R¹⁰ represents a C₁-C₆ haloalkyl, —C(O)R¹⁴, —C(O)OR¹⁴, phenyl, phenylsubstituted by (Z)_(p1), D-3, D-4, D-18, D-42, D-45, D-46, D-48 or D-49;

R¹¹ represents a hydrogen atom, C₁-C₆ alkyl or C₃-C₆ alkynyl;

R¹² represents a C₁-C₆ alkyl, phenyl or phenyl substituted by (Z)_(p1);

R¹³ represents a C₁-C₄ alkyl, and each R¹³ may be the same as ordifferent from each other when q1, q2, q3 or q4 represents an integer of2 or more, and moreover represents that two R¹³s may form oxo togetherwhen the two R¹³s are bonded to the same carbon atom;

R¹⁴ represents a C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl (C₁-C₄)alkyl, C₃-C₆ cycloalkyl, C₃-C₆ alkenyl or C₃-C₆ alkynyl;

R¹⁵ represents a hydrogen atom or C₁-C₆ alkyl;

R¹⁶ represents a —OH, C₁-C₄ alkoxy or C₁-C₄ alkylthio;

R¹⁷ represents a hydrogen atom, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆alkenyl, C₃-C₆ haloalkenyl, C₃-C₆ alkynyl, —C(R⁵)═NOR¹⁹, —C(O)OR¹⁹,—C(O)NH₂, —C(O)N(R⁵)R¹⁹, —C(O)NHC(O)R¹⁹, —C(O)N(R⁵)C(O)OR¹⁹, —N(R²¹)R²⁰,phenyl substituted by (Z)_(p1), D9 to D11, D18 to D20, D42 to D47 orD48;

R¹⁸ represents a hydrogen atom, C₁-C₆ alkyl, C₃-C₆ alkynyl,—C(O)R^(19a), —C(O)OR^(19a) or C₁-C₆ haloalkylthio;

R¹⁹ represents a C₁-C₆ alkyl, C₁-C₆ haloalkyl or C₂-C₆ alkenyl;

R^(19a) represents a C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₄ alkoxy (C₁-C₄)alkyl, C₁-C₄ alkylthio (C₁-C₄) alkyl, C₁-C₄ alkylsulfinyl (C₁-C₄) alkyl,C₁-C₄ alkylsulfonyl (C₁-C₄) alkyl, C₃-C₆ cycloalkyl, C₂-C₆ alkenyl,C₁-C₆ alkoxycarbonyl, phenyl, phenyl substituted by (Z)_(p1), D42, D43or D44;

R²⁰ represents a C₁-C₆ haloalkyl, C₁-C₆ alkoxycarbonyl, phenyl, phenylsubstituted by (Z)_(p1), D42 to D46 or D47;

R²¹ represents a hydrogen atom, C₁-C₆ alkyl, C₃-C₆ alkenyl or C₃-C₆alkynyl;

L² represents a single bond or C₁-C₆ alkylene chain;

Q² represents a hydrogen atom, C₁-C₆ haloalkyl, C₂-C₆ alkynyl,—N(R²³)R²², —C(O)N(R²³)R²², phenyl, phenyl substituted by (Z)_(p1), D18to D20, D42 to D46 or D47;

R²² represents a C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₃-C₆alkenyl, C₃-C₆ alkynyl, phenyl or phenyl substituted by (Z)_(p1);

R²³ represents a hydrogen atom or C₁-C₆ alkyl;

p1 represents an integer of 1 to 5;

p2 represents an integer of 0 to 4;

p3 represents an integer of 0 to 3;

p4 represents an integer of 0 to 2;

p5 represents an integer of 0 or 1;

q2 represents an integer of 0 to 5;

q3 represents an integer of 0 to 7;

q4 represents an integer of 0 to 9;

r represents an integer of 0 to 2;

t represents an integer of 0 or 1) and hydroxylamine in an aliphatic oran aromatic hydrocarbon solvent which may be substituted by a halogenatom by adding an additive selected from a phase-transfer catalyst, aC₁-C₆ alcohol and an aprotic polar solvent in the presence of a base andwater.

[2] The method for producing according to [1], the additive is aphase-transfer catalyst.

[3] The method for producing according to [1], the additive is a C₁-C₆alcohol.

[4] The method for producing according to [1], the additive is anaprotic polar solvent.

[5] The method for producing according to [1] to [4], the1,3-bis(substituted phenyl)-3-substituted-2-propen-1-one compoundrepresented by Formula (2) and produced by reacting, in the presence ofa dehydration agent and a base, 1,3-bis(substitutedphenyl)-3-substituted-3-hydroxypropan-1-one compound represented byFormula (3):

(where R¹, R², X, A¹, A², A³, A⁴, A⁵, A⁶ and A⁷ represent the samemeaning as described above) is used.[6] A method for producing a 1,3-bis(substitutedphenyl)-3-substituted-2-propen-1-one compound represented by Formula (2)includes reacting a 1,3-bis(substitutedphenyl)-3-substituted-3-hydroxypropan-1-one compound represented byFormula (3) in the presence of a dehydration agent and a base.[7] The method for producing according to [5] or [6], the1,3-bis(substituted phenyl)-3-substituted-3-hydroxypropan-1-one compoundis used that is represented by Formula (3) and produced by reacting anaromatic ketone compound represented by Formula (4):

(where R¹, X, A⁵, A⁶ and A⁷ represent the same meaning as describedabove) and a substituted acetophenone compound represented by Formula(5):

(where R², A¹, A², A³ and A⁴ represent the same meaning as describedabove) in a suspended state in the presence or absence of an additiveand in the presence of a base in a solvent.[8] A method for producing a 1,3-bis(substitutedphenyl)-3-substituted-3-hydroxypropan-1-one compound represented byFormula (3) is characterized by reacting an aromatic ketone compoundrepresented by Formula (4) and a substituted acetophenone compoundrepresented by Formula (5) in a suspended state in the presence orabsence of an additive and in the presence of a base in a solvent.[9] The method for producing according to [8] is characterized in thatthe solvent is an organic solvent and the reaction is conducted in theabsence of the additive.[10] The method for producing according to [8] is characterized in thatthe solvent is water and the reaction is conducted in the presence of awater-soluble organic solvent as the additive.[11] The method for producing according to [8] is characterized in thatthe solvent is water and the reaction is conducted in the presence of asurfactant as the additive.[12] A method for producing a 1,3-bis(substitutedphenyl)-3-substituted-2-propen-1-one compound represented by Formula (2)in one step includes reacting an aromatic ketone compound represented byFormula (4) and a substituted acetophenone compound represented byFormula (5) in an organic solvent, in the presence of a base, at atemperature of over 80° C.[13] A compound represented by Formula (2), wherein R¹, X, A¹, A², A³,A⁴, A⁵, A⁶ and A⁷ represent the same meaning as described above, and R²represents a substituent selected from the —S(O)_(r)-L²-Q² and D-1 toD-50.[14] A compound represented by Formula (3), wherein R¹, X, A¹, A², A³,A⁴, A⁵, A⁶ and A⁷ represent the same meaning as described above, and R²represents a substituent selected from the —S(O)_(r)-L²-Q² and D-1 toD-50.[15] A compound represented by Formula (2), wherein R¹, X, A⁵, A⁶ and A⁷represent the same meaning as described above, and at least one of A¹,A², A³ and A⁴ is N, and R² is a halogen atom.[16] A compound represented by Formula (3), wherein R¹, X, A⁵, A⁶ and A⁷represent the same meaning as described above, and at least one of A¹,A², A³ and A⁴ is N, and R² is a halogen atom.

Effects of the Invention

By the method for production according to the present invention, a1,3-bis(substituted phenyl)-3-substituted-3-hydroxypropan-1-one compoundand a 1,3-bis(substituted phenyl)-3-substituted-2-propen-1-one compoundwhich are useful for synthesizing a production intermediate offunctional materials of medical drugs, agricultural chemicals,electronic materials or the like can be produced in high yield and highselectivity, in a solvent such as water and toluene which is easy to usein industry, by utilizing an aromatic ketone compound and a substitutedacetophenone compound as starting raw materials by adequately selectinga surfactant, a dehydration agent and a base. Therefore the presentinvention can provide methods useful for industrial production.

Moreover, the present invention can provide methods for producingagricultural chemicals, particularly an isoxazoline compound describedin WO 05/085216 pamphlet which has excellent insecticidal-miticidalactivity to harmful insects for agriculture, spider mites, external orinternal parasitic insects of mammals and birds and its productionintermediate.

BEST MODES FOR CARRYING OUT THE INVENTION

The compound described in the present specification has E-form andZ-form geometric isomers depending on their substituents. However, thepresent invention includes these E-form, Z-form or E-form, and Z-form inany ratio. Moreover, the compound described in the present specificationhas an optically active substance generated by the presence of one ormore asymmetric carbon atom(s), and the compound described in thepresent specification includes every optically active substance orracemic substance.

Among the compounds described in the present specification, examples ofcompounds which can produce acid addition salts by common methodsinclude salts of hydrohalic acids such as hydrofluoric acid,hydrochloric acid, hydrobromic acid and hydroiodic acid; salts ofinorganic acids such as nitric acid, sulfuric acid, phosphoric acid,chloric acid and perchloric acid; salts of sulfonic acids such asmethanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonicacid, benzenesulfonic acid and p-toluenesulfonic acid; salts ofcarboxylic acids such as formic acid, acetic acid, propionic acid,trifluoroacetic acid, fumaric acid, tartaric acid, oxalic acid, maleicacid, malic acid, succinic acid, benzoic acid, mandelic acid, ascorbicacid, lactic acid, gluconic acid and citric acid; or salts of aminoacids such as glutamic acid and asparaginic acid.

Among the compounds described in the present specification, examples ofcompounds which can produce metal salts by common methods include saltsof alkali metals such as lithium, sodium and potassium; salts ofalkaline earth metals such as calcium, barium and magnesium; or salts ofaluminum.

Among the compounds described in the present specification, examples ofcompounds which can produce amine salts by common methods include saltsof ammonia, methylamine, ethylamine, propylamine, butylamine,pentylamine, benzylamine, aniline, dimethylamine, diethylamine,dipropylamine, dibutylamine, dipentylamine, pyrrolidine, piperidine,piperazine, morpholine, dibenzylamine, trimethylamine, triethylamine,tripropylamine, tributylamine, tripentylamine and tribenzylamine.

Next, specific examples of each substituent described in the presentspecification will be described below. Here, n-, i-, s- and t-meannormal, iso, secondary and tertiary, respectively, and ph means phenyl.

Halogen atoms in the compounds described in the present specificationinclude a fluorine atom, a chlorine atom, a bromine atom and an iodineatom. Here, the expression “halo” in the present specification alsorepresents these halogen atoms.

The expression C_(a)-C_(b) alkyl in the present specification representshydrocarbon groups of linier chains or branched chains having a to bpieces of carbon atoms. Specific examples include a methyl group, ethylgroup, n-propyl group, i-propyl group, n-butyl group, i-butyl group,s-butyl group, t-butyl group, n-pentyl group, 1-methylbutyl group,2-methylbutyl group, 3-methylbutyl group, 1-ethylpropyl group,1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropylgroup, n-hexyl group, 1-methylpentyl group, 2-methylpentyl group,1,1-dimethylbutyl group, 1,3-dimethylbutyl group, heptyl group, octylgroup, nonyl group, decyl group, undecyl group and dodecyl group. Eachof the groups is selected within the range of each specified number ofcarbon atoms.

Specific examples of the expression of aromatic heterocyclic groups inthe present specification include a 2-thienyl group, 3-thienyl group,2-furyl group, 3-furyl group, 2-pyranyl group, 3-pyranyl group,4-pyranyl group, 2-benzofuranyl group, 3-benzofuranyl group,4-benzofuranyl group, 5-benzofuranyl group, 6-benzofuranyl group,7-benzofuranyl group, 1-isobenzofuranyl group, 4-isobenzofuranyl group,5-isobenzofuranyl group, 2-benzothienyl group, 3-benzothienyl group,4-benzothienyl group, 5-benzothienyl group, 6-benzothienyl group,7-benzothienyl group, 1-isobenzothienyl group, 4-isobenzothienyl group,5-isobenzothienyl group, 2-chromenyl group, 3-chromenyl group,4-chromenyl group, 5-chromenyl group, 6-chromenyl group, 7-chromenylgroup, 8-chromenyl group, 1-pyrrolyl group, 2-pyrrolyl group, 3-pyrrolylgroup, 1-imidazolyl group, 2-imidazolyl group, 4-imidazolyl group,1-pyrazolyl group, 3-pyrazolyl group, 4-pyrazolyl group, 2-thiazolylgroup, 4-thiazolyl group, 5-thiazolyl group, 3-isothiazolyl group,4-isothiazolyl group, 5-isothiazolyl group, 2-oxazolyl group, 4-oxazolylgroup, 5-oxazolyl group, 3-isoxazolyl group, 4-isoxazolyl group,5-isoxazolyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group,2-pyrazinyl group, 2-pyrimidinyl group, 4-pyrimidinyl group,5-pyrimidinyl group, 3-pyridazinyl group, 4-pyridazinyl group,1-indolizinyl group, 2-indolizinyl group, 3-indolizinyl group,5-indolizinyl group, 6-indolizinyl group, 7-indolizinyl group,8-indolizinyl group, 1-isoindolyl group, 4-isoindolyl group,5-isoindolyl group, 1-indolyl group, 2-indolyl group, 3-indolyl group,4-indolyl group, 5-indolyl group, 6-indolyl group, 7-indolyl group,1-indazolyl group, 2-indazolyl group, 3-indazolyl group, 4-indazolylgroup, 5-indazolyl group, 6-indazolyl group, 7-indazolyl group,1-purinyl group, 2-purinyl group, 3-purinyl group, 6-purinyl group,7-purinyl group, 8-purinyl group, 2-quinolyl group, 3-quinolyl group,4-quinolyl group, 5-quinolyl group, 6-quinolyl group, 7-quinolyl group,8-quinolyl group, 1-isoquinolyl group, 3-isoquinolyl group,4-isoquinolyl group, 5-isoquinolyl group, 6-isoquinolyl group,7-isoquinolyl group, 8-isoquinolyl group, 1-phthalazinyl group,5-phthalazinyl group, 6-phthalazinyl group, 2-naphthyridinyl group,3-naphthyridinyl group, 4-naphthyridinyl group, 2-quinoxalinyl group,5-quinoxalinyl group, 6-quinoxalinyl group, 2-quinazolinyl group,4-quinazolinyl group, 5-quinazolinyl group, 6-quinazolinyl group,7-quinazolinyl group, 8-quinazolinyl group, 3-cinnolinyl group,4-cinnolinyl group, 5-cinnolinyl group, 6-cinnolinyl group, 7-cinnolinylgroup, 8-cinnolinyl group, 2-pteridinyl group, 4-pteridinyl group,6-pteridinyl group and 7-pteridinyl group and 3-furazanyl group.

Specific examples of the expression of aryl groups in the presentspecification include a phenyl group, naphthyl group, anthryl and theabove-described aromatic heterocyclic groups.

Examples of heterocyclic groups in the present specification include a2-tetrahydrofuranyl group, 3-tetrahydrofuranyl group,2-tetrahydropyranyl group, 3-tetrahydropyranyl group,4-tetrahydropyranyl group, 1-pyrrolidinyl group, 2-pyrrolidinyl group,3-pyrrolidinyl group, 1-pyrrolinyl group, 2-pyrrolinyl group,3-pyrrolinyl group, 4-pyrrolinyl group, 5-pyrrolinyl group,1-imidazolidinyl group, 2-imidazolidinyl group, 4-imidazolidinyl group,1-imidazolinyl group, 2-imidazolinyl group, 4-imidazolinyl group,1-pyrazolidinyl group, 3-pyrazolidinyl group, 4-pyrazolidinyl group,1-pyrazolinyl group, 2-pyrazolinyl group, 3-pyrazolinyl group,4-pyrazolinyl group, 5-pyrazolinyl group, 1-piperidyl group, 2-piperidylgroup, 3-piperidyl group, 4-piperidyl group, 1-piperazinyl group,2-piperazinyl group, 3-piperazinyl group, 1-indolinyl group, 2-indolinylgroup, 3-indolinyl group, 4-indolinyl group, 5-indolinyl group,6-indolinyl group, 7-indolinyl group, 1-isoindolinyl group,2-isoindolinyl group, 4-isoindolinyl group, 5-isoindolinyl group,2-quinuclidinyl group, 3-quinuclidinyl group, 4-quinuclidinyl group,2-morpholinyl group, 3-morpholinyl group, 4-morpholinyl group,1-azetidinyl group, 2-azetidinyl group, 3-azetidinyl group,1-azetidinonyl group, 3-azetidinonyl group and 4-azetidinonyl group,other than the above-described aromatic heterocyclic groups.

The expression C_(a)-C_(b) haloalkyl in the present specificationrepresents hydrocarbon groups of linier chains or branched chains havinga to b pieces of carbon atoms in which hydrogen atom(s) bonding tocarbon atom(s) is optionally substituted by halogen atom(s). In thiscase, these halogen atoms may be the same as or different from eachother, when the alkyl group is substituted by 2 or more halogen atoms.Specific examples include a fluoromethyl group, chloromethyl group,bromomethyl group, iodomethyl group, difluoromethyl group,chlorofluoromethyl, dichloromethyl group, bromofluoromethyl group,trifluoromethyl group, chlorodifluoromethyl group, dichlorofluoromethylgroup, trichloromethyl group, bromodifluoromethyl group,bromochlorofluoromethyl group, dibromofluoromethyl group, 2-fluoroethylgroup, 2-chloroethyl group, 2-bromoethyl group, 2,2-difluoroethyl group,2-chloro-2-fluoroethyl group, 2,2-dichloroethyl group,2-bromo-2-fluoroethyl group, 2,2,2-trifluoroethyl group,2-chloro-2,2-difluoroethyl group, 2,2-dichloro-2-fluoroethyl group,2,2,2-trichloroethyl group, 2-bromo-2,2-difluoroethyl group,2-bromo-2-chloro-2-fluoroethyl group, 2-bromo-2,2-dichloroethyl group,1,1,2,2-tetrafluoroethyl group, pentafluoroethyl group,1-chloro-1,2,2,2-tetrafluoroethyl group,2-chloro-1,1,2,2-tetrafluoroethyl group,1,2-dichloro-1,2,2-trifluoroethyl group,2-bromo-1,1,2,2-tetrafluoroethyl group, 2-fluoropropyl group,2-chloropropyl group, 2-bromopropyl group, 2-chloro-2-fluoropropylgroup, 2,3-dichloropropyl group, 2-bromo-3-fluoropropyl group,3-bromo-2-chloropropyl group, 2,3-dibromopropyl group,3,3,3-trifluoropropyl group, 3-bromo-3,3-difluoropropyl group,2,2,3,3-tetrafluoropropyl group, 2-chloro-3,3,3-trifluoropropyl group,2,2,3,3,3-pentafluoropropyl group, 1,1,2,3,3,3-hexafluoropropyl group,heptafluoropropyl group, 2,3-dichloro-1,1,2,3,3-pentafluoropropyl group,2-fluoro-1-methylethyl group, 2-chloro-1-methylethyl group,2-bromo-1-methylethyl group, 2,2,2-trifluoro-1-(trifluoromethyl)ethylgroup, 1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl group, 2-fluorobutylgroup, 2-chlorobutyl group, 2,2,3,3,4,4-hexafluorobutyl group,2,2,3,4,4,4-hexafluorobutyl group, 2,2,3,3,4,4-hexafluorobutyl group,2,2,3,3,4,4,4-heptafluorobutyl group, 1,1,2,2,3,3,4,4-octafluorobutylgroup, nonafluorobutyl group, 4-chloro-1,1,2,2,3,3,4,4-octafluorobutylgroup, 2-fluoro-2-methylpropyl group,1,2,2,3,3,3-hexafluoro-1-(trifluoromethyl)propyl group,2-chloro-1,1-dimethylethyl group, 2-bromo-1,1-dimethylethyl group,5-chloro-2,2,3,4,4,5,5-heptafluoropentyl group, and tridecafluorohexylgroup. Each of the groups is selected within the range of each specifiednumber of carbon atoms.

The expression cyano (C_(a)-C_(b)) alkyl in the present specificationrepresents alkyl groups of linier chains or branched chains having a tob pieces of carbon atoms in which hydrogen atom(s) bonding to carbonatom(s) is optionally substituted by a cyano group. Specific examplesinclude, a cyanomethyl group, 1-cyanoethyl group, 2-cyanoethyl group,2-cyanopropyl group, 3-cyanopropyl group and 2-cyanobutyl group. Each ofthe groups is selected within the range of each specified number ofcarbon atoms.

The expression C_(a)-C_(b) cycloalkyl in the present specificationrepresents cyclic hydrocarbon groups having a to b pieces of carbonatoms, and can form a 3-membered ring to a 6-membered ring of monocyclicor composite ring structures. In addition, each ring may be optionallysubstituted by an alkyl group within a range of each specified number ofcarbon atoms. Specific examples include a cyclopropyl group,1-methylcyclopropyl group, 2-methylcyclopropyl group,2,2-dimethylcyclopropyl group, 2,2,3,3-tetramethylcyclopropyl group,cyclobutyl group, cyclopentyl group, 2-methylcyclopentyl group,3-methylcyclopentyl group, cyclohexyl group, 2-methylcyclohexyl group,3-methylcyclohexyl group, 4-methylcyclohexyl group andbicyclo(2.2.1)heptane-2-yl group. Each of the groups is selected withthe range of each specified number of carbon atoms.

The expression C_(a)-C_(b) halocycloalkyl in the present specificationrepresents cyclic hydrocarbon groups having a to b pieces of carbonatoms in which hydrogen atom(s) bonding to carbon atom(s) is optionallysubstituted by halogen atom(s), and can form a 3-membered ring to a6-membered ring of monocyclic or composite ring structures. In addition,each ring may be optionally substituted by an alkyl group within a rangeof each specified number of carbon atoms, and a ring structure part, aside chain part or both of them may be substituted by halogen atom(s).Moreover, these halogen atoms may be the same as or different from eachother, when the cycloalkyl group is substituted by 2 or more halogenatoms. Specific examples include a 2,2-difluorocyclopropyl group,2,2-dichlorocyclopropyl group, 2,2-dibromocyclopropyl group,2,2-difluoro-1-methylcyclopropyl group, 2,2-dichloro-1-methylcyclopropylgroup, 2,2-dibromo-1-methylcyclopropyl group,2,2,3,3-tetrafluorocyclobutyl group, 2-(trifluoromethyl)cyclohexylgroup, 3-(trifluoromethyl)cyclohexyl group and4-(trifluoromethyl)cyclohexyl group. Each of the groups is selectedwithin the range of each specified number of carbon atoms.

The expression C_(a)-C_(b) alkenyl in the present specificationrepresents unsaturated hydrocarbon groups of linier chains or branchedchains having a to b pieces of carbon atoms and having one or moredouble bond(s) in the molecule. Specific examples include a vinyl group,1-propenyl group, 2-propenyl group, 1-methylethenyl group, 2-butenylgroup, 1-methyl-2-propenyl group, 2-methyl-2-propenyl group, 2-pentenylgroup, 2-methyl-2-butenyl group, 3-methyl-2-butenyl group,2-ethyl-2-propenyl group, 1,1-dimethyl-2-propenyl group, 2-hexenylgroup, 2-methyl-2-pentenyl group, 2,4-dimethyl-2,6-heptadienyl group and3,7-dimethyl-2,6-octadienyl group. Each of the groups is selected withinthe range of each specified number of carbon atoms.

The expression C_(a)-C_(b) haloalkenyl in the present specificationrepresents unsaturated hydrocarbon groups of linier chains or branchedchains having a to b pieces of carbon atoms in which hydrogen atom(s)bonding to carbon atom(s) is optionally substituted by halogen atom(s)and having one or more double bond(s) in the molecule. In this case,these halogen atoms may be the same as or different from each other,when the alkenyl group is substituted by 2 or more halogen atoms.Specific examples include a 2,2-dichlorovinyl group, 2-fluoro-2-propenylgroup, 2-chloro-2-propenyl group, 3-chloro-2-propenyl group,2-bromo-2-propenyl group, 3-bromo-2-propenyl group,3,3-difluoro-2-propenyl group, 2,3-dichloro-2-propenyl group,3,3-dichloro-2-propenyl group, 2,3-dibromo-2-propenyl group,2,3,3-trifluoro-2-propenyl group, 2,3,3-trichloro-2-propenyl group,1-(trifluoromethyl) ethenyl group, 3-chloro-2-butenyl group,3-bromo-2-butenyl group, 4,4-difluoro-3-butenyl group,3,4,4-trifluoro-3-butenyl group, 3-chloro-4,4,4-trifluoro-2-butenylgroup and 3-bromo-2-methyl-2-propenyl group. Each of the groups isselected within the range of each specified number of carbon atoms.

The expression C_(a)-C_(b) alkynyl in the present specificationrepresents unsaturated hydrocarbon groups of linier chains or branchedchains having a to b pieces of carbon atoms and having one or moretriple bond(s) in the molecule. Specific examples include an ethynylgroup, 1-propynyl group, 2-propynyl group, 2-butynyl group,1-methyl-2-propynyl group, 2-pentynyl group, 1-methyl-2-butynyl group,1,1-dimethyl-2-propynyl group and 2-hexynyl group. Each of the groups isselected within the range of each specified number of carbon atoms.

The expression C_(a)-C_(b) alkoxy in the present specificationrepresents alkyl-O— groups, in which the alkyl has a to b pieces ofcarbon atoms as defined above. Specific examples include a methoxygroup, ethoxy group, n-propyloxy group, i-propyloxy group, n-butyloxygroup, i-butyloxy group, s-butyloxy group, t-butyloxy group, n-pentyloxygroup and n-hexyloxy group. Each of the groups is selected within therange of each specified number of carbon atoms.

The expression C_(a)-C_(b) haloalkoxy in the present specificationrepresents haloalkyl-O-groups, in which the haloalkyl has a to b piecesof carbon atoms as defined above. Specific examples include adifluoromethoxy group, trifluoromethoxy group, chlorodifluoromethoxygroup, bromodifluoromethoxy group, 2-fluoroethoxy group, 2-chloroethoxygroup, 2,2,2-trifluoroethoxy group, 1,1,2,2-tetrafluoroethoxy group,2-chloro-1,1,2-trifluoroethoxy group, 2-bromo-1,2,2-trifluoroethoxygroup, pentafluoroethoxy group, 2,2-dichloro-1,1,2-trifluoroethoxygroup, 2,2,2-trichloro-1,1-difluoroethoxy group,2-bromo-1,1,2,2-tetrafluoroethoxy group, 2,2,3,3-tetrafluoropropyloxygroup, 1,1,2,3,3,3-hexafluoropropyloxy group,2,2,2-trifluoro-1-(trifluoromethyl)ethoxy group, heptafluoropropyloxygroup and 2-bromo-1,1,2,3,3,3-hexafluoropropyloxy group. Each of thegroups is selected within the range of each specified number of carbonatoms.

The expression C_(a)-C_(b) alkylthio in the present specificationrepresents alkyl-S— groups, in which the alkyl has a to b pieces ofcarbon atoms as defined above. Specific examples include a methylthiogroup, ethylthio group, n-propylthio group, i propylthio group,n-butylthio group, i-butylthio group, s-butylthio group, t-butylthiogroup, n-pentylthio group and n-hexylthio group. Each of the groups isselected within the range of each specified number of carbon atoms.

The expression C_(a)-C_(b) haloalkylthio in the present specificationrepresents haloalkyl-S-groups, in which the haloalkyl has a to b piecesof carbon atoms as defined above. Specific examples include adifluoromethylthio group, trifluoromethylthio group,chlorodifluoromethylthio group, bromodifluoromethylthio group,2,2,2-trifluoroethylthio group, 1,1,2,2-tetrafluoroethylthio group,2-chloro-1,1,2-trifluoroethylthio group, pentafluoroethylthio group,2-bromo-1,1,2,2-tetrafluoroethylthio group,1,1,2,3,3,3-hexafluoropropylthio group, heptafluoropropylthio group,1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethylthio group andnonafluorobutylthio group. Each of the groups is selected within therange of each specified number of carbon atoms.

The expression C_(a)-C_(b) alkylsulfinyl in the present specificationrepresents alkyl-S(O)-groups, in which the alkyl has a to b pieces ofcarbon atoms as defined above. Specific examples include amethylsulfinyl group, ethylsulfinyl group, n-propylsulfinyl group,i-propylsulfinyl group, n-butylsulfinyl group, i-butylsulfinyl group,s-butylsulfinyl group and t-butylsulfinyl group. Each of the groups isselected within the range of each specified number of carbon atoms.

The expression C_(a)-C_(b) haloalkylsulfinyl in the presentspecification represents haloalkyl-S(O)-groups, in which the haloalkylhas a to b pieces of carbon atoms as defined above. Specific examplesinclude a difluoromethylsulfinyl group, trifluoromethylsulfinyl group,chlorodifluoromethylsulfinyl group, bromodifluoromethylsulfinyl group,2,2,2-trifluoroethylsulfinyl group,2-bromo-1,1,2,2-tetrafluoroethylsulfinyl group,1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethylsulfinyl group andnonafluorobutylsulfinyl group. Each of the groups is selected within therange of each specified number of carbon atoms.

The expression C_(a)-C_(b) alkylsulfonyl in the present specificationrepresents alkyl-SO₂-groups, in which the alkyl has a to b pieces ofcarbon atoms as defined above. Specific examples include amethylsulfonyl group, ethylsulfonyl group, n-propylsulfonyl group,i-propylsulfonyl group, n-butylsulfonyl group, i-butylsulfonyl group,s-butylsulfonyl group, t-butylsulfonyl group, n-pentylsulfonyl group andn-hexylsulfonyl group. Each of the groups is selected within the rangeof each specified number of carbon atoms.

The expression C_(a)-C_(b) haloalkylsulfonyl in the presentspecification represents haloalkyl-SO₂-groups, in which the haloalkylhas a to b pieces of carbon atoms as defined above. Specific examplesinclude a difluoromethylsulfonyl group, trifluoromethylsulfonyl group,chlorodifluoromethylsulfonyl group, bromodifluoromethylsulfonyl group,2,2,2-trifluoroethylsulfonyl group, 1,1,2,2-tetrafluoroethylsulfonylgroup, 2-chloro-1,2,2-trifluoroethylsulfonyl group and2-bromo-1,1,2,2-tetrafluoroethylsulfonyl group. Each of the groups isselected within the range of each specified number of carbon atoms.

The expression C_(a)-C_(b) alkylcarbonyl in the present specificationrepresents alkyl-C(O)-groups, in which the alkyl has a to b pieces ofcarbon atoms as defined above. Specific examples include an acetylgroup, propionyl group, butyryl group, isobutyryl group, valeryl group,isovaleryl group, 2-methylbutanoyl group, pivaloyl group, hexanoyl groupand heptanoyl group. Each of the groups is selected within the range ofeach specified number of carbon atoms.

The expression C_(a)-C_(b) haloalkylcarbonyl in the presentspecification represents haloalkyl-C(O)-groups, in which the haloalkylhas a to b pieces of carbon atoms as defined above. Specific examplesinclude a fluoroacetyl group, chloroacetyl group, difluoroacetyl group,dichloroacetyl group, trifluoroacetyl group, chlorodifluoroacetyl group,bromodifluoroacetyl group, trichloroacetyl group, pentafluoropropionylgroup, heptafluorobutanoyl group and 3-chloro-2,2-dimethylpropanoylgroup. Each of the groups is selected within the range of each specifiednumber of carbon atoms.

The expression C_(a)-C_(b) alkoxycarbonyl in the present specificationrepresents alkyl-O—C(O)-groups, in which the alkyl has a to b pieces ofcarbon atoms as defined above. Specific examples include amethoxycarbonyl group, ethoxycarbonyl group, n-propyloxycarbonyl group,i-propyloxycarbonyl group, n-butoxycarbonyl group, i-butoxycarbonylgroup and t-butoxycarbonyl group. Each of the groups is selected withinthe range of each specified number of carbon atoms.

The expression C_(a)-C_(b) alkylthiocarbonyl in the presentspecification represents alkyl-S—C(O)-groups, in which the alkyl has ato b pieces of carbon atoms as defined above. Specific examples includea methylthio-C—(O)— group, ethylthio-C—(O)— group, n-propylthio-C—(O)—group, i-propylthio-C—(O)— group, n-butylthio-C—(O)— group,i-butylthio-C—(O)— group and t-butylthio-C—(O)— group. Each of thegroups is selected within the range of each specified number of carbonatoms.

The expression C_(a)-C_(b) alkoxythiocarbonyl in the presentspecification represents alkyl-O—C(S)-groups, in which the alkyl has ato b pieces of carbon atoms as defined above. Specific examples includea methoxy-C(S)— group, ethoxy-C(S)— group, n-propyloxy-C(S)— group andi-propyloxy-C(S)— group. Each of the groups is selected within the rangeof each specified number of carbon atoms.

The expression C_(a)-C_(b) alkyldithiocarbonyl in the presentspecification represents alkyl-S—C(S)-groups, in which the alkyl has ato b pieces of carbon atoms as defined above. Specific examples includea methylthio-C(S)— group, ethylthio-C(S)— group, n-propylthio-C(S)—group and i-propylthio-C(S)— group. Each of the groups is selectedwithin the range of each specified number of carbon atoms.

The expression C_(a)-C_(b) alkylaminocarbonyl in the presentspecification represents carbamoyl groups whose one hydrogen atom issubstituted by an alkyl group, in which the alkyl has a to b pieces ofcarbon atoms as defined above. Specific examples include amethylcarbamoyl group, ethylcarbamoyl group, n-propylcarbamoyl group,i-propylcarbamoyl group, n-butylcarbamoyl group, i-butylcarbamoyl group,s-butylcarbamoyl group, and t-butylcarbamoyl group. Each of the groupsis selected within the range of each specified number of carbon atoms.

The expression di(C_(a)-C_(b) alkyl) aminocarbonyl in the presentspecification represents carbamoyl groups whose both hydrogen atoms aresubstituted by alkyl groups which may be the same as or different fromeach other and have a to b pieces of carbon atoms as defined above.Specific examples include an N,N-dimethylcarbamoyl group,N-ethyl-N-methylcarbamoyl group, N,N-diethylcarbamoyl group,N,N-di-n-propylcarbamoyl group and N,N-di-n-butylcarbamoyl group. Eachof the groups is selected within the range of each specified number ofcarbon atoms.

The expression C_(a)-C_(b) alkylaminosulfonyl in the presentspecification represents sulfamoyl group whose one hydrogen atom issubstituted by an alkyl group which has a to b pieces of carbon atoms asdefined above. Specific examples include a methylsulfamoyl group,ethylsulfamoyl group, n-propylsulfamoyl group, i-propylsulfamoyl group,n-butylsulfamoyl group, i-butylsulfamoyl group, s-butylsulfamoyl groupand t-butylsulfamoyl group. Each of the groups is selected within therange of each specified number of carbon atoms.

The expression di(C_(a)-C_(b) alkyl) aminosulfonyl in the presentspecification represents sulfamoyl groups whose both hydrogen atoms aresubstituted by alkyl groups which may be the same as or different fromeach other and have a to b pieces of carbon atoms as defined above.Specific examples include an N,N-dimethylsulfamoyl group,N-ethyl-N-methylsulfamoyl group, N,N-diethylsulfamoyl group,N,N-di-n-propylsulfamoyl group and N,N-di-n-butylsulfamoyl group. Eachof the groups is selected within the range of each specified number ofcarbon atoms.

The expression C_(a)-C_(b) cycloalkyl(C_(d)-C_(e)) alkyl, C_(a)-C_(b)alkoxy(C_(d)-C_(e)) alkyl or C_(a)-C_(b) alkylthio(C_(d)-C_(e)) alkyl inthe present specification represents a hydrocarbon group of liner chainsor branched chains whose hydrogen atoms bonding to carbon atoms areoptionally substituted by a C_(a)-C_(b) cycloalkyl group, C_(a)-C_(b)alkoxy group or C_(a)-C_(b) alkylthio group as defined above, and whosenumber of substituted carbon atoms is d-e. Each of the groups isselected within the range of each specified number of carbon atoms.

The expression (C_(a)-C_(b)) alkyl optionally substituted by R⁸ in thepresent specification represents hydrocarbon groups of linier chains orbranched chains, whose hydrogen atoms bonding to carbon atom(s) isoptionally substituted by any R⁸, and whose number of substituted carbonatoms is a-b. Each of the groups is selected within the range of eachspecified number of carbon atoms. In this case, these R⁸s may be thesame as or different from each other, when the substituent R⁸ on each(C_(a)-C_(b)) alkyl groups are 2 or more.

The expression hydroxy (C_(d)-C_(e)) haloalkyl, C_(a)-C_(b) alkoxy(C_(d)-C_(e)) haloalkyl or C_(a)-C_(b) haloalkoxy (C_(d)-C_(e))haloalkyl in the present specification represents haloalkyl groups whosehydrogen atoms or halogen atoms bonding to carbon atoms are optionallysubstituted by any C_(a)-C_(b) alkoxy group, C_(a)-C_(b) haloalkoxygroup or hydroxy group as defined above, and whose number of substitutedcarbon atoms is d-e. Specific examples include a2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl group,difluoro(methoxy)methyl group,2,2,2-trifluoro-1-methoxy-1-(trifluoromethyl)ethyl group,difluoro(2,2,2-trifluoroethoxy)methyl group,2,2,2-trifluoro-1-(2,2,2-trifluoroethoxy)-1-(trifluoromethyl)ethylgroup, and3-(1,2-dichloro-1,2,2-trifluoroethoxy)-1,1,2,2,3,3-hexafluoropropylgroup. Each of the groups is selected within the range of each specifiednumber of carbon atoms.

In the compounds described in the present specification, examples of asubstituent represented by X preferably include a halogen atom and C₁-C₄haloalkyl, and more preferably include a chlorine atom, bromine atom,iodine atom and trifluoromethyl. In this case, each X may be the same asor different from each other, when m which represents the number ofsubstituents represented by X represents an integer of 2 or more.

In the compounds described in the present specification, m whichrepresents the number of substituents represented by X is preferably 1,2, and 3.

In the compounds described in the present specification, a position of asubstituent represented by X is preferably the meta position or paraposition to the bonding position of a carbon to which R¹ is bonded.

In the compounds described in the present specification, examples of asubstituent represented by Y preferably include a halogen atom, nitro,C₁-C₄ alkyl and C₁-C₄ haloalkyl, and more preferably include a fluorineatom, chlorine atom, bromine atom, iodine atom, nitro, methyl, ethyl andtrifluoromethyl. In this case, each Y may be the same as or differentfrom each other, when n represents an integer of 2.

In the compounds described in the present specification, n whichrepresents the number of substituents represented by Y is preferably 0and 1.

In the compounds described in the present specification, a position ofsubstituent represented by Y is more preferably the ortho position tothe bonding position of R².

In the compounds described in the present specification, examples of asubstituent represented by R¹ preferably include a C₁-C₄ haloalkyl, morepreferably include a difluoromethyl, chlorodifluoromethyl,bromodifluoromethyl and trifluoromethyl, and extremely preferablyinclude a chlorodifluoromethyl and trifluoromethyl.

In the compounds described in the present specification, examples of asubstituent represented by R² preferably include a methyl, a halogenatom, cyano, nitro, —NH₂, —NHR⁴, —OH, —OR³, benzyloxy, —OSO₂R³,phenylsulfonyloxy, p-toluenesulfonyloxy, —C(O)OH, —C(O)OR³, —C(O)NH₂,—C(O)N(R^(1b))R^(1a), -L-Q, -L-N(R^(1c))R^(1d), D-1 to D-50 or—S(O)_(r)-L²-Q², and more preferably include a methyl, chlorine atom,bromine atom, iodine atom, cyano, nitro, amino, —NHR⁴, hydroxy, methoxy,methoxymethyloxy, acetyloxy, benzyloxy, methanesulfonyloxy,trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, —C(O)OH,methoxycarbonyl, ethoxycarbonyl, —C(O)NH², —C(O)N(R^(1b))R^(1a), -L-Q,-L-N(R^(1c))R^(1d), G or —S(O)_(r)-L²-Q²,

In the compounds described in the present specification, examples of asubstituent represented by R³ preferably include a C₁-C₄ alkyl, C₁-C₄alkoxy (C₁-C₄) alkyl and C₁-C₄ haloalkyl, and more preferably include amethyl, ethyl, methoxymethyl, methoxyethyl, ethoxymethyl andtrifluoromethyl.

In the compounds described in the present specification, examples of asubstituent represented by R⁴ preferably include a —CHO, C₁-C₄alkylcarbonyl and C₁-C₄ alkoxycarbonyl, and more preferably include aformyl, acetyl, propionyl, methoxycarbonyl and ethoxycarbonyl.

In the compounds described in the present specification, an example of asubstituent represented by R⁵ preferably includes a hydrogen atom.

In the compounds described in the present specification, examples of asubstituent represented by R^(1a) preferably include a C₁-C₄ alkyloptionally substituted by R⁸, —N(R¹¹)R¹⁰, —C(O)OR⁹, —C(O)NH₂, —C(O)NHR⁹,—C(R⁷)═NOR⁶, phenyl, phenyl substituted by (Z)_(p1), D-5, D-7, D-10,D-11, D-12, D-14, D-15, D-18, D-31, D-32, D-42, D-43, D-45, D-46, D-48,E-1 or E-7.

In the compounds described in the present specification, examples of asubstituent represented by R^(1b) preferably include a hydrogen atom,C₁-C₆ alkyl, C₁-C₄ alkoxy (C₁-C₄) alkyl, cyano (C₁-C₄) alkyl, C₃-C₆alkynyl, —C(O)R⁹ and —C(O)OR⁹, and more preferably include a hydrogenatom, methyl, ethyl, methoxymethyl, cyanomethyl, propargyl, acetyl,propionyl, butyryl, pivaloyl, methoxycarbonyl and ethoxycarbonyl.

In the compounds described in the present specification, examples of asubstituent represented by R⁸ preferably include a halogen atom, cyano,C₃-C₆ cycloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, —C(O)N(R¹⁵)R¹⁴,—C(R⁷)═NOR⁶, phenyl, phenyl substituted by (Z)_(p1), D-11 to D-14, D-18,D-19, D-25, D-26, D-31, D-32, D-36, D42, D-45, D-48, D-49, E-1, E-2 orE-5, and more preferably include a fluorine atom, chlorine atom, bromineatom, cyano, cyclopropyl, methoxy, ethoxy, 2,2,2-trifluoroethoxy,—C(O)N(R¹⁵)R¹⁴, —CH═NOCH₃, phenyl, phenyl substituted by (Z)_(p1), D-14,D-19, D-31, D-32, D-36, D-42 and E-5.

In the compounds described in the present specification, examples of asubstituent represented by Z preferably include a halogen atom, cyano,nitro, C₁-C₄ alkyl, C₁-C₄ haloalkyl and C₁-C₄ haloalkoxy, and morepreferably include a fluorine atom, chlorine atom, bromine atom, cyano,nitro, methyl, trifluoromethyl and trifluoromethoxy. In this case, eachZ may be the same as or different from each other, when p1, p2, p3 or p4which represents the number of substituents represented by Z representsan integer of 2 or more.

In the compounds described in the present specification, p1 whichrepresents the number of substituents represented by Z preferablyincludes 1 and 2.

In the compounds described in the present specification, p2 whichrepresents the number of substituents represented by Z preferablyincludes 0 and 1.

In the compounds described in the present specification, p3 whichrepresents the number of substituents represented by Z preferablyincludes 0 and 1.

In the compounds described in the present specification, p4 whichrepresents the number of substituents represented by Z preferablyincludes 0 and 1.

In the compounds described in the present specification, p5 whichrepresents the number of substituents represented by Z preferablyincludes 0 and 1.

In the compounds described in the present specification, examples of asubstituent represented by R⁶ preferably include a C₁-C₄ alkyl, and morepreferably include a methyl and ethyl.

In the compounds described in the present specification, examples of asubstituent represented by R⁷ preferably include a hydrogen atom andC₁-C₄ alkyl, and more preferably include a hydrogen atom and methyl.

In the compounds described in the present specification, examples of asubstituent represented by R⁹ preferably include a C₁-C₄ alkyl, C₁-C₄haloalkyl, C₁-C₄ alkoxy (C₁-C₄) alkyl, C₁-C₄ alkylthio (C₁-C₄) alkyl,C₃-C₈ cycloalkyl, C₃-C₆ alkenyl and C₃-C₆ alkynyl, more preferablyinclude a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl,t-butyl, trifluoromethyl, chloroethyl, 2,2,2-trifluoroethyl,methoxymethyl, ethoxymethyl, methoxyethyl, methylthiomethyl,cyclopropyl, allyl and propargyl.

In the compounds described in the present specification, examples of asubstituent represented by R¹⁰ preferably include a C₁-C₄ haloalkyl,—C(O)R¹⁴, —C(O)OR¹⁴, phenyl, phenyl substituted by (Z)_(p1), D-3, D-4,D18, D-42, D-45, D-46, D-48 or D-49, and more preferably include a2,2,2-trifluoroethyl, —C(O)R¹⁴, —C(O)OR¹⁴, phenyl, phenyl substituted by(Z)_(p1), D-18, D-42 and D-45.

In the compounds described in the present specification, examples of asubstituent represented by R¹¹ preferably include a hydrogen atom, C₁-C₆alkyl and C₃-C₆ alkynyl, and more preferably include a hydrogen atom,methyl, ethyl and propargyl.

In the compounds described in the present specification, examples of asubstituent represented by R¹² preferably include a C₁-C₄ alkyl, andmore preferably include methyl and ethyl.

In the compounds described in the present specification, examples of asubstituent represented by R¹³ preferably include a C₁-C₄ alkyl, andmore preferably include a methyl. In this case, each R¹³ may be the sameas or different from each other, when p1, p2, p3 or p4 which representsthe number of substituents represented by R¹³ represents an integer of 2or more. In addition, two R¹³s may together form oxo, when the two R¹³sare substituted on the same carbon atom.

In the compounds described in the present specification, q2 whichrepresents the number of substituents represented by R¹³ preferablyincludes 1 and 2.

In the compounds described in the present specification, q3 whichrepresents the number of substituents represented by R¹³ preferablyincludes 0, 1 and 2.

In the compounds described in the present specification, q4 whichrepresents the number of substituents represented by R¹³ preferablyincludes 0, 1 and 2.

In the compounds described in the present specification, examples of asubstituent represented by R¹⁴ preferably include a C₁-C₄ alkyl, C₁-C₄haloalkyl, C₃-C₆ cycloalkyl (C₁-C₄) alkyl, C₃-C₆ cycloalkyl, C₃-C₆alkenyl and C₃-C₆ alkynyl, and more preferably include a methyl, ethyl,2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2,2-trifluoroethyl,cyclopropylmethyl, cyclopropyl, allyl and propargyl.

In the compounds described in the present specification, examples of asubstituent represented by R¹⁵ preferably include a hydrogen atom andC₁-C₄ alkyl, and more preferably include a hydrogen, methyl and ethyl.

In the compounds described in the present specification, r whichrepresents the number of oxygen on a sulfur atom includes 0, 1 and 2.

In the compounds described in the present specification, t whichrepresents the number of oxygen on a nitrogen atom in a pyridine ringincludes 0 and 1.

In the compounds described in the present specification, examples of Lpreferably include a —CH₂—, —CH(CH₃)—, —CH(CN)—, —CH(R^(2a))CH₂— (whereR^(2a) represents a hydrogen atom, cyano or C₁-C₆ alkyl), —N(R^(2c))—and —CH(R^(2a))N(R^(2c))— (where R^(2a) represents a hydrogen atom,cyano or C₁-C₆ alkyl and R^(2c) represents a hydrogen atom, C₁-C₆ alkyl,C₁-C₆ alkylcarbonyl, C₁-C₆ haloalkylcarbonyl or C₃-C₆ cycloalkylcarbonyl), and particularly preferably include a —CH₂—, —CH(CH₃)— and—CH(CN)—.

In the compounds described in the present specification, examples ofR^(1c) include a hydrogen atom, —C(O)R^(3a), —C(O)OR^(3a), —C(O)SR^(3a),—C(O)N(R^(3b))R^(3a), —C(S)N(R^(3b))R^(3a) or —S(O)₂R^(3a), andparticularly preferably include a —C(O)R^(3a), —C(O)OR^(3a) and—C(O)N(R^(3b))R^(3a).

In the compounds described in the present specification, examples ofR^(1d) preferably include a hydrogen atom, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₄ alkoxy (C₁-C₄) alkyl, C₁-C₄ haloalkoxy (C₁-C₄) alkyl, C₁-C₄alkylthio (C₁-C₄) alkyl, C₁-C₄ alkylsulfonyl (C₁-C₄) alkyl, cyano(C₁-C₆) alkyl, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkyl (C₁-C₄) alkyl, C₃-C₆alkenyl, C₃-C₆ alkynyl, —C(O)R^(3c), —C(O)OR^(3c), —C(O)SR^(3c), C₁-C₆haloalkylthio or C₁-C₆ alkylsulfonyl, and particularly preferablyinclude a hydrogen atom, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₄ alkoxy(C₁-C₄) alkyl, C₁-C₄ haloalkoxy (C₁-C₄) alkyl, C₃-C₆ cycloalkyl (C₁-C₄)alkyl and —C(O)R^(3c).

Examples of R^(3a) include a C₁-C₆ alkyl, C₁-C₆ haloalkyl, (C₁-C₄) alkyloptionally substituted by R^(4a), C₃-C₆ cycloalkyl, C₃-C₆halocycloalkyl, E-1, E-2, E-4, C₂-C₆ alkenyl, C₂-C₆ haloalkenyl, C₂-C₆alkynyl, phenyl, phenyl substituted by (V)_(p1), D-3, D-4, D-12 to D-14,D-42 or D-43, and particularly preferably include a C₁-C₆ alkyl, C₁-C₆haloalkyl, (C₁-C₄) alkyl optionally substituted by R^(4a), C₃-C₆cycloalkyl, C₃-C₆ halocycloalkyl, phenyl and phenyl substituted by(V)_(p1).

Examples of R^(3b) include a hydrogen atom and C₁-C₆ alkyl.

Examples of R^(3c) include a hydrogen atom C₁-C₄ alkyl, C₁-C₄ haloalkyl,C₃-C₆ cycloalkyl (C₁-C₄) alkyl, C₃-C₆ cycloalkyl, C₃-C₆ alkenyl or C₃-C₆alkynyl, or include the case that R^(3c) forms a 5-7 membered ring witha nitrogen atom, carbon atom, oxygen atom or sulfur atom to be bonded,by forming an ethylene chain or benzene ring bonded at ortho-positiontogether with R^(3a).

Examples of R^(4a) include a halogen atom, cyano, nitro, C₃-C₆cycloalkyl, C₁-C₄ alkoxy, C₁-C₆ alkoxycarbonyl, S(O)_(r)R^(5a), D-42 orD-43.

Examples of R^(5a) include C₁-C₄ alkyl.

Examples of V include a halogen atom, cyano, nitro, C₁-C₆ alkyl, C₁-C₆haloalkyl, —OH, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ alkylsulfonyloxy,C₁-C₆ haloalkylsulfonyloxy, C₁-C₆ alkylthio, C₁-C₆ haloalkylthio, C₁-C₆alkylsulfinyl, C₁-C₆ haloalkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆haloalkylsulfonyl, —NH₂, C₁-C₆ alkylamino, di(C₁-C₆ alkyl) amino, C₁-C₆alkoxycarbonyl, —C(O)NH₂, C₁-C₆ alkylaminocarbonyl, C₁-C₆haloalkylaminocarbonyl, di(C₁-C₆ alkyl) aminocarbonyl, —C(S)NH₂,—S(O)₂NH₂, C₁-C₆ alkylaminosulfonyl or di(C₁-C₆ alkyl) aminosulfonyl,and each V may be the same as or different from each other, when p1represents an integer of 2 or more, and moreover, when two Vs areadjacent, the two adjacent Vs may form a 5-membered ring or a 6-memberedring with carbon atoms bonding to each of the two Vs by forming —O—CH₂O—or —OCH₂CH₂O—, and hydrogen atoms bonding to each carbon atom formingthe ring may be optionally substituted by halogen atoms in this case.

Examples of Z include a halogen atom, cyano, nitro, amino, C₁-C₆ alkyl,(C₁-C₆) alkyl optionally substituted by R¹⁶, C₁-C₆ haloalkyl, C₁-C₆alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ alkylthio, C₁-C₆ haloalkylthio, C₁-C₆alkylsulfinyl, C₁-C₆ haloalkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆haloalkylsulfonyl, C₁-C₆ alkoxycarbonyl, —C(O)NH₂, —C(S)NH₂, —S(O)₂NH₂,—C(O)N(R¹⁸)R¹⁷, —C(S)N(R¹⁸)R¹⁷, C₁-C₆ alkylaminosulfonyl or di (C₁-C₆alkyl) aminosulfonyl, and preferably include a halogen atom, C₁-C₆alkyl, C₁-C₆ alkylthio, C₁-C₆ alkylsulfinyl, C₁-C₆ haloalkylsulfinyl,C₁-C₆ alkylsulfonyl and C(O)N(R¹⁸)R¹⁷.

Examples of L² preferably include a single bond, methylene, ethylidene,propylidene, 1-methyl-ethyliden, butylidene, 1-methyl-propylidene,2-methyl-propylidene, pentylidene, 1-methylbutylidene,2-methylbutylidene, 3-methylbutylidene, hexylidene, ethylene,trimethylene, tetramethylene, pentamethylene and hexamethylene.

Examples of Q² include a hydrogen atom, C₁-C₆ haloalkyl, C₂-C₆ alkynyl,—N(R²³)R²², —C(O)N(R²³)R²², phenyl, phenyl substituted by (Z)_(p1), D18to D20 or D-42 to D47, and preferably include a hydrogen atom, C₁-C₆haloalkyl, C₂-C₆ alkynyl, —N(R²³)R²², —C(O)N(R²³)R²² and D42 to D47.

Specific examples of the expression of (R^(1b) may form a 3-7 memberedring with a nitrogen atom to be bonded, by forming a C₂-C₆ alkylenechain together with R^(1a), and this alkylene chain may include oneoxygen atom, sulfur atom or nitrogen atom in this case) in the presentspecification include an aziridine, azetidine, pyrrolidine, oxazolidine,thiazolidine, imidazolidine, piperidine, morpholine, thiomorpholine,piperazine, homopiperizine, and heptamethyleneimine, each of which isselected within the range of each specified number of atoms.

Specific examples of the expression of (R^(1c) may form a 5-7 memberedring with a nitrogen atom to be bonded, by forming a C₄-C₆ alkylenechain together with R^(1d), and this alkylene chain may include oneoxygen atom, sulfur atom or nitrogen atom in this case, and may beoptionally substituted by an oxo group or thioxo group) in the presentspecification include an aziridine, azetidine, azetidine-2-one,pyrrolidine, pyrrolidine-2-one, oxazolidine, oxazolidine-2-one,oxazolidine-2-thione, thiazolidine, thiazolidine-2-one,thiazolidine-2-thione, imidazolidine, imidazolidine-2-one,imidazolidine-2-thione, piperidine, piperidine-2-one,piperidine-2-thione, 2H-3,4,5,6-tetrahydro-1,3-oxazin-2-one,2H-3,4,5,6-tetrahydro-1,3-oxazin-2-thione, morpholine,2H-3,4,5,6-tetrahydro-1,3-thiazine-2-one,2H-3,4,5,6-tetrahydro-1,3-thiazine-2-thione, thiomorpholine,perhydropyrimidine-2-one, piperazine, homopiperizine,homopiperizine-2-one and heptamethyleneimine, each of which is selectedwithin the range of each specified number of atoms.

Specific examples of the expression of (R^(2a) may form a 3-6 memberedring with a nitrogen atom to be bonded, by forming a C₂-C₅ alkylenechain together with R^(2b), and this alkylene chain may include oneoxygen atom, sulfur atom or nitrogen atom in this case) in the presentspecification include a cyclopropane ring, cyclobutane ring,cyclopentane ring, tetrahydrofuran ring, tetrahydrothiophene ring,pyrrolidine ring, cyclohexane ring, tetrahydropyran ring,tetrahydrothiopyran ring, piperidine ring, cycloheptane ring, oxepanering, thiepane ring and azepane ring. Each of the rings is selectedwithin the range of each specified number of atoms.

Examples of solvents capable to be used for the reactions during theproduction of (2) from (3), the production of (3) from (4) and (5) andthe production of (2) from (4) and (5) in one step according to thepresent invention include aromatic hydrocarbons which may be substitutedby halogen atoms such as benzene, toluene, xylene, chlorobenzene,o-dichlorobenzene or mesitylene; or aliphatic hydrocarbons which may besubstituted by halogen atoms such as n-pentane, n-hexane, n-heptane,n-octane, cyclopentane, cyclohexane, methylcyclohexane, methylenechloride or 1,2-dichloroethane; ethers such as diethyl ether,diisopropyl ether, cyclopentyl methyl ether, t-butyl methyl ether;nitriles such as acetonitrile and propionitrile; esters such as ethylacetate and butyl acetate; amines such as triethylamine, tributylamineand pyridine; nitromethane; nitroethane; water and a supercriticalfluid, and preferably include toluene, n-hexane, n-heptane, cyclohexane,methylene chloride, 1,2-dichloroethane, chlorobenzene, diisopropylether, cyclopentyl methyl ether, t-butyl methyl ether, acetonitrile,propionitrile, ethyl acetate, butyl acetate, triethylamine,tributylamine, pyridine, nitromethane, water or the supercritical carbondioxide, and particularly preferably include toluene for the productionof (2) from (3); water, chlorobenzene, toluene, n-heptane, tributylamineor ethyl acetate for the production of (3) from (4) and (5); and toluenefor the production of (2) from (4) and (5) in one step. These solventsmay be used singly or in combination.

An amount used of such solvents is not particularly limited. However,the amount is usually 0.01 to 100 parts by weight, preferably 0.05 to 50parts by weight, and particularly preferably 0.1 to 15 parts by weightper part by weight of the aromatic ketone compound or the substitutedacetophenone compound or the 1,3-bis(substitutedphenyl)-3-substituted-3-hydroxypropan-1-one compound.

Examples of bases capable to be used for the reaction according to thepresent invention include sodium hydroxide, potassium hydroxide, bariumhydroxide, calcium hydroxide, potassium carbonate, sodium carbonate,barium carbonate, calcium carbonate, potassium bicarbonate, sodiumbicarbonate, sodium acetate, potassium acetate, sodium methoxide,potassium-t-butoxide, ammonia, methylamine, ethylamine, n-propylamine,i-propylamine, n-butylamine, i-butylamine, t-butylamine, n-pentylamine,i-pentylamine, benzylamine, aniline, dimethylamine, diethylamine,di-n-propylamine, di-i-propylamine, di-n-butylamine, di-i-butylamine,di-n-pentylamine, di-i-pentylamine, pyrrolidine, piperidine, piperazine,morpholine, dibenzylamine, trimethylamine, triethylamine,tri-n-propylamine, tri-n-butylamine, tripentylamine, tribenzylamine,diisopropylethylamine, N-methylmorpholine, pyridine,2-methyl-5-ethylpyridine, 4-dimethylaminopyridine, 1,8-diazabicyclo(5,4,0)-7-undecene, triethylenediamine,N,N,N′,N′-tetramethylethylenediamine or 1,1,3,3-tetramethylguanidine,and preferably include pyridine, 2-methyl-5-ethylpyridine, tributylamineand 4-dimethylaminopyridine, for the production of (2) from (3);diethylamine, di-i-propylamine, di-n-propylamine, di-n-butylamine,pyrrolidine, triethylamine, tri-n-butylamine for the production of (3)from (4) and (5) performed in an organic solvent; potassium carbonateand sodium carbonate for the production of (3) from (4) and (5)performed in water; potassium carbonate, sodium carbonatetri-n-butylamine, 4-dimethylaminopyridine, 1,8-diazabicyclo(5,4,0)-7-undecene and 1,1,3,3-tetramethylguanidine for the productionof (2) from (4) and (5) in one step. These bases may be used singly orin combination.

An amount used of such bases is not particularly limited. However, theamount is usually 0.01 to 100 times by mole, preferably 0.05 to 50 timesby mole, particularly preferably 0.05 to 10 times by mole per mol of the1,3-bis(substituted phenyl)-3-substituted-3-hydroxypropan-1-one compoundfor the production of (2) from (3), and usually 0.01 to 50 times bymole, preferably 0.05 to 25 times by mole, particularly preferably 0.05to 5 times by mole per mol of the aromatic ketone compound or thesubstituted acetophenone compound for the production of (3) from (4) and(5), and the production of (2) from (4) and (5) in one step.

Examples of surfactants or the like capable to be used for the reactionaccording to the present invention as additives include as follows:

(A) Nonionic Surfactant:

(A-1) Polyethylene glycol type surfactants: Examples of polyethyleneglycol type surfactants include polyoxyethylenealkyl (C₁₂₋₁₈) ether, anethyleneoxide adduct of alkylnaphthol, polyoxyethylene (mono or di)alkyl (C₈₋₁₂) phenyl ether, formaldehyde condensation products ofpolyoxyethylene (mono or di) alkyl (C₈₋₁₂) phenyl ether, polyoxyethylene(mono, di, or tri) phenyl phenyl ether, polyoxyethylene (mono, di ortri) benzyl phenyl ether, polyoxypropylene (mono, di, or tri) benzylphenyl ether, polyoxyethylene (mono, di, or tri) styryl phenyl ether,polyoxypropylene (mono, di or tri) styryl phenyl ether, a polymer ofpolyoxyethylene (mono, di or tri) styryl phenyl ether, a polyoxyethylenepolyoxypropylene block polymer, an alkyl (C₁₂₋₁₈) polyoxyethylenepolyoxypropylene block polymer ether, an alkyl (C₈₋₁₂) phenylpolyoxyethylene polyoxypropylene block polymer ether, polyoxyethylenebisphenyl ether, polyoxyethylene resin acid ester, polyoxyethylene fattyacid (C₁₂₋₁₈) monoester, polyoxyethylene fatty acid (C₁₂₋₁₈) diester,polyoxyethylene sorbitan fatty acid (C₁₂₋₁₈) ester, ethyleneoxide adductof glycerol fatty acid ester, ethyleneoxide adduct of castor oil,ethyleneoxide adduct of hardened caster oil, ethyleneoxide adduct ofalkyl (C₁₂₋₁₈) amine and ethyleneoxide adduct of fatty acid (C₁₂₋₁₈)amide.

(A-2) Polyvalent alcohol type surfactants: Examples of polyvalentalcohol type surfactants include glycerol fatty acid ester, polyglycerinfatty acid ester, pentaerythritol fatty acid ester, sorbitol fatty acid(C₁₂₋₁₈) ester, sorbitan fatty acid (C₁₂₋₁₈) ester, sucrose fatty acidester, polyvalent alcohol alkyl ether and fatty acid alkanol amide.

(A-3) Acetylene type surfactants: Examples of acetylene type surfactantsinclude acetylene glycol, acetylene alcohol, ethyleneoxide adduct ofacetylene glycol and ethyleneoxide adduct of acetylene alcohol.

(A-4) Other surfactants: Examples of other surfactants includealkylglucoside.

(B) Anionic Surfactants:

(B-1) Carboxylic acid type surfactants: Examples of carboxylic acid typesurfactants include polyacrylic acid, polymethacrylic acid, polymaleicacid, a copolymer of maleic acid and olefin (for example, isobutyleneand diisobutylene), a copolymer of acrylic acid and itaconic acid, acopolymer of methacrylic acid and itaconic acid, a copolymer of maleicacid and styrene, a copolymer of acrylic acid and methacrylic acid, acopolymer of acrylic acid and methyl acrylate, a copolymer of acrylicacid and vinyl acetate, a copolymer of acrylic acid and maleic acid,N-methyl-fatty acid (C₁₂₋₁₈) sarcosinate, carboxylic acids such as resinacid and fatty acid (C₆₋₂₀) and the like, and salts of these carboxylicacids.

(B-2) Sulfate ester type surfactants: Examples sulfate ester typesurfactants include alkyl (C₁₂₋₁₈) sulfate ester, polyoxyethylene alkyl(C₁₂₋₁₈) ether sulfate ester, polyoxyethylene (mono or di) alkyl (C₈₋₁₂)phenyl ether sulfate ester, sulfate ester of a polyoxyethylene (mono ordi) alkyl (C₁₂₋₁₈) phenyl ether polymer, polyoxyethylene (mono, di, ortri) phenyl phenyl ether sulfate ester, polyoxyethylene (mono, di, ortri) benzyl phenyl ether sulfate ester, polyoxyethylene (mono, di, ortri) styryl phenyl ether sulfate ester, sulfate ester of apolyoxyethylene (mono, di, or tri) styryl phenyl ether polymer, sulfateester of a polyoxyethylene polyoxypropylene block polymer, sulfated oil,sulfated fatty acid ester, sulfated fatty acid and sulfate ester ofsulfated olefin and the like, and salts of these sulfate esters.

(B-3) Sulfonic acid type surfactants: Examples of sulfonic acid typesurfactants include paraffin (C₁₂₋₂₂) sulfonic acid, alkyl (C₈₋₁₂)benzene sulfonic acid, formaldehyde condensation products of alkyl(C₈₋₁₂) benzene sulfonic acid, formaldehyde condensation products ofcresol sulfonic acid, α-olefin (C₁₄₋₁₆) sulfonic acid, dialkyl (C₈₋₁₂)sulfosuccinic acid, lignin sulfonic acid, polyoxyethylene (mono or di)alkyl (C₈₋₁₂) phenyl ether sulfonic acid, polyoxyethylenealkyl (C₁₂₋₁₈)ether sulfosuccinate half ester, naphthalene sulfonic acid, (mono, ordi) alkyl (C₁₋₆) naphthalene sulfonic acid, formaldehyde condensationproducts of naphthalene sulfonic acid, formaldehyde condensationproducts of (mono, or di) alkyl (C₁₋₆) naphthalene sulfonic acid,formaldehyde condensation products of creosote oil sulfonic acid, alkyl(C₈₋₁₂) diphenyl ether disulfonic acid, Igepon T (trade name),polystyrene sulfonic acid and sulfonic acids of a styrene sulfonicacid-methacrylic acid copolymer and the like, and salts of thesesulfonic acids

(B-4) Phosphate ester type surfactants: Examples of phosphate ester typesurfactants include alkyl (C₁₂₋₁₈) phosphate ester, polyoxyethylenealkyl (C₁₂₋₁₈) ether phosphate ester, polyoxyethylene (mono or di) alkyl(C₈₋₁₂) phenyl ether phosphate ester, phosphate ester of apolyoxyethylene (mono, di, or tri) alkyl (C₈₋₁₂) phenyl ether polymer,polyoxyethylene (mono, di, or tri) phenyl phenyl ether phosphate ester,polyoxyethylene (mono, di, or tri) benzyl phenyl ether phosphate ester,polyoxyethylene (mono, di, or tri) styryl phenyl ether phosphate ester,phosphate ester of a polyoxyethylene (mono, di, or tri) styryl phenylether polymer, phosphate ester of a polyoxyethylene polyoxypropyleneblock polymer, phosphatidylcholine, phosphatidyl ethanolimine andphosphate ester of condensed phosphoric acid (for example,tripolyphosphoric acid) and the like, and salts of these phosphateesters.

Salts of above-mentioned (B-1) to (B-4) include alkaline metals (such aslithium, sodium and potassium), alkaline earth metals (such as calciumand magnesium), ammonium and various types of amines (such as alkylamines, cycloalkyl amines and alkanol amines).

(C) Cationic Surfactants:

Examples of cationic surfactants include alkyl amine salts and alkylquaternary ammonium salts.

(D) Amphoteric Surfactants:

Examples of amphoteric surfactants include betaine type surfactants andamino acid type surfactants.

(E) Other Surfactants:

Examples of other surfacants include silicone type surfactant andfluorine type surfactant. Preferable examples include Soprofol(anionic/nonionic surfactant, trade name of Rhodia Nicca, Ltd.), Solpol3353 (nonionic surfactant, trade name of Toho Chemical Industry Co.,Ltd.), Epan (polyoxyethylene polyoxypropylene glycol, trade name ofDai-ichi Kogyo Seiyaku Co., Ltd.), tetrabutylammonium bromide,cetylpyridinium chloride, dodecyltrimethylammonium chloride,dodecylamine hydrochloride, sodium dodecyl sulfate, sodiumdodecanesulfonate, dodecylbenzenesulfonic acid or the salt thereof,p-toluenesulfonic acid or the salt thereof, polyethylene glycol,hexanoic acid or the salt thereof, octanoic acid or the salt thereof,decanoic acid or the salt thereof, lauric acid or the salt thereof,myristic acid or the salt thereof, palmitic acid or the salt thereof,stearic acid or the salt thereof, oleic acid or the salt thereof,proline or the salt thereof and phenylalanine or the salt thereof.

Examples of the salts include alkali metals (lithium, sodium andpotassium), alkaline earth metals (calcium and magnesium), ammonium andpyridinium.

Such surfactants are usually 0.0001 to 1 times by mole, preferably 0.001to 1 times by mole, particularly preferably 0.01 to 0.5 times by moleper mol of the aromatic ketone compound (4) or the substitutedacetophenone compound (5).

Examples of water soluble organic solvents capable to be used for thereaction according to the present invention as additives includedimethylsulfoxide, sulfolane, N,N-dimethylformamide,N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N,N′-dimethylethyleneurea, hexamethylphosphoric triamide, acetonitrile, propionitrile,methanol, ethanol or nitromethane, and preferably dimethyl sulfoxide,sulfolane, N,N-dimethylformamide, hexamethylphosphoric triamide,acetonitrile, methanol or nitromethane, and particularly preferablyN,N-dimethylacetamide, acetonitrile or methanol. These may be usedsingly or in combination.

An amount used of such water organic soluble solvents is usually 0.01 to10 parts by weight, preferably 0.05 to 5 parts by weight, andparticularly preferably 0.05 to 3 parts by weight per part by weight ofthe aromatic ketone compound or the substituted acetophenone compound.

Examples of compounds capable to be used for the reaction according tothe present invention as dehydration agents include thionyl chloride,sulfuric chloride, methanesulfonyl chloride, p-toluenesulfonyl chloride,benzoyl chloride, acetyl chloride, acetic anhydride, propionic anhydrideor benzoic anhydride, and preferably thionyl chloride, sulfuricchloride, methanesulfonyl chloride, benzoyl chloride, acetyl chloride,acetic anhydride or benzoic anhydride.

An amount used of such dehydration agents is usually 0.1 to 100 times bymole, preferably 0.5 to 50 times by mole, particularly preferably 1 to15 times by mole per mol of the 1,3-bis(substitutedphenyl)-3-substituted-3-hydroxypropan-1-one compound.

For performing the production of (2) from (3) according to the presentinvention, for example, 1,3-bis(substitutedphenyl)-3-substituted-3-hydroxypropan-1-one compound represented byFormula (3) or the salt thereof, a solvent as represented by toluene, abase as represented by triethylamine, tri-n-butylamine, pyridine and4-dimethylaminopyridine, a dehydration agent as represented by thionylchloride and acetic anhydride are fed into a reactor, and the mixturemay be stirred for usually about 10 minutes to 150 hours, and preferablyabout 1 to 96 hour(s) usually at 0 to 150° C. and preferably at 20 to120° C.

For performing the production of (3) from (4) and (5) or the productionof (2) from (4) and (5) in one step according to the present invention,for example, a predetermined amount of the aromatic ketone compoundrepresented by Formula (4) and the substituted acetophenone compoundrepresented by Formula (5), a solvent as represented by toluene, a baseas represented by triethylamine and tri-n-butylamine are fed into areactor, and the mixture may be stirred for usually about 10 minutes to150 hours, and preferably about 1 to 96 hour(s) usually at 0 to 150° C.and preferably at 20 to 100° C.

For example, a predetermined amount of the aromatic ketone compoundrepresented by Formula (4) and the substituted acetophenone compoundrepresented by Formula (5), water, a base as represented by potassiumcarbonate and a water soluble organic solvent are fed into a reactor,and the mixture may be stirred for usually about 10 minutes to 150hours, and preferably about 1 to 96 hour(s) usually at 0 to 100° C. andpreferably at 20 to 100° C.

For example, a predetermined amount of the aromatic ketone compoundrepresented by Formula (4) and the substituted acetophenone compoundrepresented by Formula (5), water, a base as represented by potassiumcarbonate, a surfactant and the like are fed into a reactor, and themixture may be stirred for usually about 10 minutes to 150 hours, andpreferably about 1 to 96 hour(s) usually at 0 to 100° C. and preferablyat 20 to 100° C.

For example, a predetermined amount of the aromatic ketone compoundrepresented by Formula (4) and the substituted acetophenone compoundrepresented by Formula (5), a solvent as represented by toluene and abase as represented by potassium carbonate are fed into a reactor, andthe mixture may be stirred for usually about 10 minutes to 150 hours,and preferably about 1 to 120 hour(s) usually at 0 to 150° C. andpreferably at 20 to 120° C.

For example, a predetermined amount of the aromatic ketone compoundrepresented by Formula (4) and the substituted acetophenone compoundrepresented by Formula (5), a solvent as represented by toluene, a baseas represented by tri-n-butylamine and 4-dimethylaminopyridine, adehydration agent as represented by benzoic anhydride are fed into areactor, and the mixture may be stirred for usually about 10 minutes to150 hours, and preferably about 1 to 120 hour(s) usually at 0 to 150° C.and preferably at 20 to 120° C.

Among them, preferable embodiments include, for example, the case thatthe solvent is an organic solvent and the reaction is performed withoutadditives; the case that the solvent is water and the reaction isperformed with an water soluble organic solvent as the additive; and thecase that the solvent is water and the reaction is performed with asurfactant as the additive.

Here, for producing (2) through (3) from (4) and (5) in one pot, it ispreferable that an organic solvent is used as the solvent, and thereaction temperature is set to a temperature of over 80° C. In addition,(2) can also be produced in one step by adding a dehydration agent asrepresented by benzoic anhydride to the reaction solution withoutisolating (3) produced from (4) and (5).

The compound represented by Formula (4) can be produced, for example, bythe following method.

More specifically, a known compound represented by General Formula (6)(where X represents the same meaning as described above, and A⁵, A⁶ andA⁷ independently represent C—X) and a known compound represented byGeneral Formula (7) (where R¹ represents the same meaning as describedabove, and J⁴ represents a leaving group such as a halogen atom,trifluoromethanesulfonyloxy group and 2-pyridyloxy group) or a knowncompound represented by General Formula (8) (where R¹ represents thesame meaning as described above) are reacted by the common aromatic ringacylation reactions described in documents, for example, in accordancewith the methods described in “Chemistry Letters (Chem. Lett.)” 783(1990) and “The Journal of Organic Chemistry (J. Org. Chem.)” vol. 56,1963 (1991). As a result, a compound represented by General Formula (4)(where X, R¹, A⁵, A⁶ and A⁷ represent the same meaning as describedabove) can be obtained.

The compound represented by General Formula (4) can also be obtained by:the following methods. After a known compound represented by GeneralFormula (9) (where X represents the same meaning as described above; A⁵,A⁶ and A⁷ independently represent C—X or N; and J³ represents a bromineatom or an iodine atom) is treated with a common method described indocuments, for example, lithiated, the reactant is made to react with aknown compound represented by General Formula (10) (where R¹ representsthe same meaning as described above; J⁵ represents a halogen atom,hydroxy group, metal salts (for example, —OLi and —ONa), C₁-C₄ alkoxy(for example, methoxy group and ethoxy group), di(C₁-C₄ alkyl) aminogroup (for example diethylamino group), C₁-C₄ alkoxy (C₁-C₄ alkyl) aminogroup (for example, O,N-dimethylhydroxyamino group) or cyclicamino group(for example, piperidin-1-yl group, morpholin-4-yl group and4-methylpiperazin-1-yl)) or a known compound represented by GeneralFormula (8) in accordance with the methods described in “Journal of theAmerican Chemical Society (J. Am. Chem. Soc)” vol. 77, 3657 (1955),Tetrahedron Letters (Tetrahedron. Lett.) Vol. 21, 2129 (1980) and Vol.32, 2003 (1991) and U.S. Pat. No. 5,514,816; or after forming a Grignardreagent, the reagent is made to react with the compound represented byGeneral Formula (10) or the compound represented by General Formula (8)in accordance with the methods described in Heterocycles (Heterocycles)Vol. 25, 211 (1987), Synthetic Communications (Synth. Commun.) Vol. 15,1291 (1985) and German Patent Publication (DE 19,727,042) and the like.

In addition, in General Formula (4), General Formula (3-1), where R¹ istrifluoromethyl group, can be synthesized as follows.

More specifically, the compound represented by General Formula (4-1)(where X, A⁵, A⁶ and A⁷ represents the same meaning as described above)can also be obtained by reacting a known compound represented by GeneralFormula (11) (where X, A⁵, A⁶ and A⁷ represents the same meaning asdescribed above, and J⁶ represents a halogen atom or C₁-C₄ alkoxy group(for example methoxy group)) with a known compound represented byGeneral Formula (12) (where J⁷ represents tri(C₁-C₄ alkylsilyl group(for example trimethylsilyl group)) by the known methods described indocuments, for example, in accordance with the methods described in TheJournal of Organic Chemistry (J. Org. Chem.) vol. 64, 2873 (1999), TheJournal of Organic Chemistry (J. Org. Chem.) vol. 56, 984 (1991).

In each reaction, each production intermediate which acts as rawmaterial compound can be obtained by performing common treatment afterthe completion of the reaction.

In addition, each production intermediate produced by these methods canalso be used in an untreated state in next steps without isolation andpurification.

Examples of the solvents capable to be used in the reaction when (1) isproduced from (2) according to the present invention include aromatichydrocarbons which may be substituted by halogen atoms such as benzene,toluene, xylene, chlorobenzene, o-dichlorobenzene or mesitylene; oraliphatic hydrocarbons which may be substituted by halogen atoms such asn-pentane, n-hexane, n-heptane, n-octane, cyclopentane, cyclohexane,methylene chloride, 1,2-dichloroethane or methylcyclohexane, preferablytoluene, n-hexane, n-heptane, cyclohexane, methylene chloride orchlorobenzene, and particularly preferably toluene, n-heptane ormethylene chloride. These may be used singly or in combination.

An amount used of such solvents is not particularly limited. However,the amount is usually 0.1 to 100 parts by weight, preferably 1 to 50parts by weight, and particularly preferably 2 to 15 parts by weight perpart by weight of the 1,3-bis(substitutedphenyl)-3-substituted-2-propen-1-one compound.

Hydroxylamine may be used in the form of acid-salts such ashydrochloride, sulfate or acetate, or may also be used as an aqueoussolution of adequate concentration.

An amount used of such hydroxylamine is usually 0.5 to 100 times bymole, preferably 1 to 10 times by mole, particularly preferably 1 to 2times by mole per mol of the 1,3-bis(substitutedphenyl)-3-substituted-2-propen-1-one compound.

Examples of aprotic polar solvents capable to be used in the reactionaccording to the present invention as additives includedimethylsulfoxide, sulfolane, ethylene carbonate, propylene carbonate,N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone,N,N′-dimethylethylene urea, N,N′-dimethylpropylene urea,hexamethylphosphoric triamide, nitromethane, pyridine,2-methyl-5-ethylpyridine, triethylamine, diisopropylethylamine,tributylamine, 1,8-diazabicyclo (5,4,0)-7-undecene, 1,5-diazabicyclo(4,3,0)-5-nonene, N,N,N′,N′-tetramethylethylenediamine or nitrobenzene.These may be used singly or in combination.

An amount used of such aprotic polar solvents is usually 0.1 to 100parts by weight, preferably 0.5 to 50 parts by weight, and particularlypreferably 1 to 15 parts by weight per part by weight of1,3-bis(substituted phenyl)-3-substituted-2-propen-1-one compound.

Examples of phase-transfer catalysts capable to be used in the reactionaccording to the present invention as additives includetetrabutylammonium bromide, tetrabutylammonium chloride,tetramethylammonium chloride, tetrapropylammonium hydroxide,tetrabutylammonium hydrogen sulfate, benzyltrimethylammonium chloride,trioctylmethylammonium chloride (ALIQUATR 336), cetylpyridiniumchloride, 18-crown-6, dodecyltrimethylammonium chloride,benzyltriphenylphosphonium chloride or ethyltriphenylphosphoniumacetate.

Such phase-transfer catalysts are usually 0.0001 to 10 times by mole,and preferably 0.0005 to 1 times by mole per mol of the1,3-bis(substituted phenyl)-3-substituted-2-propen-1-one compound.

Examples of C₁-C₆ alcohol capable to be used in the reaction accordingto the present invention as additives include methanol, ethanol,propanol, isopropanol, butanol or pentanol, and preferably methanol orethanol,

An amount used of such C₁-C₆ alcohols is usually 0.1 to 100 parts byweight, preferably 0.5 to 50 parts by weight, and particularlypreferably 1 to 15 parts by weight per part by weight of the1,3-bis(substituted phenyl)-3-substituted-2-propen-1-one compound.

Examples of bases capable to be used in the reaction according to thepresent invention include sodium hydroxide, potassium hydroxide, bariumhydroxide, potassium carbonate, potassium bicarbonate, sodium carbonate,sodium bicarbonate, sodium acetate, sodium methoxide,potassium-t-butoxide, pyridine, 2-methyl-5-ethylpyridine, piperidine,triethylamine, di-isopropylethylamine, tributylamine,4-dimethylaminopyridine, 1,8-diazabicyclo (5,4,0)-7-undecene,1,5-diazabicyclo (4,3,0)-5-nonene, triethylenediamine,N,N,N′,N′-tetramethylethylenediamine, pyrrolidine or1,1,3,3-tetramethylguanidine.

For performing the reaction according to the present invention, forexample, predetermined amounts of a 1,3-bis(substitutedphenyl)-3-substituted-2-propen-1-one compound represented by Formula (2)and additives of an aprotic polar solvent, a phase-transfer catalyst andC₁-C₆ alcohol, and a solvent as represented by toluene are fed into areactor, and separately, a solution of a mixture of a base, water andhydroxylamine are added in dropwise with stirring to react for about 10minutes to 120 hours, preferably about 1 to 48 hour(s) usually at −70 to100° C., preferably −40 to 50° C.

Specific examples of aromatic ketone compounds represented by Formula(4) capable to be used as starting materials according to the presentinvention are shown in Compound List-1 below. However, the compoundsaccording to the present invention are not limited to these compounds.

Specific examples of substituted acetophenone compounds represented byFormula (5) and 1,3-bis(substituted phenyl)-3-substituted-2-propen-1-onecompounds represented by Formula (2) capable to be used as startingmaterials according to the present invention are shown in CompoundsList-2 below. However, the compounds according to the present inventionare not limited to these compounds.

Here, in Compound List-2, the expression Et represents ethyl group, andin the same manner, n-Pr and Pr-n, i-Pr and Pr-i, c-Pr and Pr-c, and Phrepresent a normalpropyl group, isopropyl group, cyclopropyl group andphenyl group, respectively.

Specific examples of the substituent Y and R² in Compound List-2 areshown in Table 1. In Table 1, aromatic heterocyclic groups representedby D-1a to D-50a represent the following structures.

For example, the expression (CH₂(D-14a)CH₃) represents a1-methylpyrazol-5-ylmethyl group, and (CH₂(D-19b)CH₃) represents a2-methylthiazol-5-ylmethyl group.

In addition, heteroaliphatic groups represented by E-1a to E-8brepresent the following structures.

For example, the expression (CH₂(E-5b)CH₃) represents a2-methy-1,3-dioxolan-2-ylmethyl group.

In Table 1, the expression “-” represents non-substitution.

TABLE 1 Y R² — CH₃ — F — Cl — Br — I — CN — NO₂ — NH₂ — NHC(O)CH₃ —NHC(O)OCH₃ — NHC(O)OEt — OH — OC(O)CH₃ — OCH₂Ph — OSO₂CH₃ — OSO₂CF₃ —OSO₂Ph — OSO₂(Ph-4-CH₃) — SCH₃ — S(O)CH₃ — SO₂CH₃ — SEt — S(O)Et — SO₂Et— SCH₂CF₃ — SPh — SCH₂(D-42a) — D-38a — D-11a — D-21a — D-35a — D-36a-H— D-36a-Me — D-36b-Me — D-39a — D-40a-H — D-40a-Me — C(O)OH — C(O)OCH₃ —C(O)OEt — C(O)NH₂ — C(O)NHCH₂Pr-c — C(O)NHCH₂CF₃ — C(O)N(CH₂OCH₃)CH₂CF₃— C(O)N[C(O)CH₃]CH₂CF₃ — C(O)N[C(O)OCH₃]CH₂CF₃ — C(O)NHCH₂CH═CH₂ —C(O)NHCH₂CH≡CH — C(O)NHCH₂CN — C(O)NHCH₂OCH₂CF₃ — C(O)NHCH₂CH₂OCH₃ —C(O)NHCH₂CH₂OEt — C(O)NHCH═NOCH₃ — C(O)NHCH═NOEt — C(O)NHCH₂CH═NOH —C(O)NHCH₂CH═NOCH₃ — C(O)NHCH₂C(O)OH — C(O)NHCH₂C(O)OCH₃ —C(O)NHCH₂C(O)NH₂ — C(O)NHCH₂C(O)NHCH₂CH₂Cl — C(O)NHCH₂C(O)NHCH₂CH₂Br —C(O)NHCH₂C(O)NHCH₂CF₃ — C(O)NHCH₂C(O)NHCH₂CH₂OH — C(O)NHCH(CH₃)C(O)OH —C(O)NHCH(CH₃)C(O)OCH₃ — C(O)NHCH(CH₃)C(O)NHCH₂CH₂Cl —C(O)NHCH(CH₃)C(O)NHCH₂CF₃ — C(O)NHPh — C(O)NH(Ph-4-F) — C(O)NH(Ph-4-CN)— C(O)NH(D-11a) — C(O)NH(D-42a) — C(O)NH(D-42d)Cl — C(O)NH(D-43e)Cl —C(O)NH(D-45a) — C(O)N(CH₃)(D-45a) — C(O)N[C(O)CH₃](D-45a) —C(O)N[C(O)OCH₃](D-45a) — C(O)NH(D-45c)Cl — C(O)N(CH₃)(D-45c)Cl —C(O)N[C(O)CH₃](D-45c)Cl — C(O)N[C(O)OCH₃](D-45c)Cl — C(O)NH(D-46a) —C(O)NH(D-48a) — C(O)NH(E-1a) — C(O)NHCH₂(D-11a) — C(O)NHCH₂(D-14a)CH₃ —C(O)NHCH₂(D-14b)Cl — C(O)NHCH₂(D-18a) — C(O)NHCH₂(D-19a) —C(O)N[C(O)CH₃]CH₂(D-19a) — C(O)N[C(O)Et]CH₂(D-19a) —C(O)N[C(O)OCH₃]CH₂(D-19a) — C(O)NHCH₂(D-25a) — C(O)NHCH₂(D-27a) —C(O)NHCH₂(D-28a) — C(O)NHCH₂(D-31a) — C(O)NHCH₂(D-34a) —C(O)NHCH₂(D-36a) — C(O)NHCH₂(D-42a) — C(O)N(CH₂CN)CH₂(D-42a) —C(O)N(CH₂OCH₃)CH₂(D-42a) — C(O)N[C(O)CH₃]CH₂(D-42a) —C(O)N[C(O)Et]CH₂(D-42a) — C(O)N[C(O)OCH₃]CH₂(D-42a) — C(O)NHCH₂(D-44a) —C(O)NHCH₂(D-45a) — C(O)NHCH₂(D-46a) — C(O)NHCH₂(D-48a) — C(O)NHCH₂(E-1a)— C(O)NHC(O)OCH₃ — C(O)N(CH₃)C(O)OCH₃ — C(O)N(Et)C(O)OCH₃ —C(O)N(CH₂CN)C(O)OCH₃ — C(O)N(CH₂OCH₃)C(O)OCH₃ — C(O)N[C(O)Et]C(O)OCH₃ —C(O)N[C(O)Pr-n]C(O)OCH₃ — C(O)N[C(O)Pr-i]C(O)OCH₃ —C(O)N[C(O)OCH₃]C(O)OCH₃ — C(O)NHC(O)OEt — C(O)N(CH₃)C(O)OEt —C(O)N(Et)C(O)OEt — C(O)N(CH₂CN)C(O)OEt — C(O)N(CH₂OCH₃)C(O)OEt —C(O)N[C(O)CH₃]C(O)OEt — C(O)N[C(O)Et]C(O)OEt — C(O)N[C(O)Pr-n]C(O)OEt —C(O)N[C(O)Pr-i]C(O)OEt — C(O)N[C(O)OCH₃]C(O)OEt — C(O)NHC(O)OPr-i —C(O)N(CH₃)C(O)OPr-i — C(O)N(Et)C(O)OPr-i — C(O)N(CH₂CN)C(O)OPr-i —C(O)N(CH₂OCH₃)C(O)OPr-i — C(O)N[C(O)CH₃]C(O)OPr-i —C(O)N[C(O)Et]C(O)OPr-i — C(O)N[C(O)Pr-n]C(O)OPr-i —C(O)N[C(O)Pr-i]C(O)OPr-i — C(O)N[C(O)OCH₃]C(O)OPr-i —C(O)N[C(O)OEt]C(O)OPr-i — C(O)NHC(O)NH₂ — C(O)NHN(CH₃)Ph —C(O)N[C(O)CH₃]N(CH₃)Ph — C(O)N[C(O)OCH₃]N(CH₃)Ph — C(O)NHN(CH₃)(D-45a) —C(O)N[C(O)CH₃]N(CH₃)(D-45a) — C(O)N[C(O)OCH₃]N(CH₃)(D-45a) — CH₂NHC(O)Pr-i — CH₂NH C(O)CF₃ — CH₂NH C(O)OEt — CH₂NH C(O)(Ph-2-CH₃) — CH₂NHC(O)NH(Ph-2-F) — CH₂N(CH₃)C(O)Me — CH₂N(i-Pr)C(O)Et — CH(CH₃)NHC(O) CHF₂— CH₂(T-1) NO₂ Cl NO₂ Br NO₂ I NO₂ CN NO₂ NH₂ NO₂ NHC(O)CH₃ NO₂NHC(O)OCH₃ NO₂ NHC(O)OEt NO₂ OH NO₂ OC(O)CH₃ NO₂ OCH₂Ph NO₂ OSO₂CH₃ NO₂OSO₂CF₃ NO₂ OSO₂Ph NO₂ OSO₂(Ph-4-CH₃) NO₂ SCH₃ NO₂ S(O)CH₃ NO₂ SO₂CH₃NO₂ SEt NO₂ S(O)Et NO₂ SO₂Et NO₂ SCH₂CF₃ NO₂ SPh NO₂ SCH₂(D-42a) NO₂D-38a NO₂ D-11a NO₂ D-21a NO₂ D-35a NO₂ D-36a-H NO₂ D-36a-Me NO₂D-36b-Me NO₂ D-39a NO₂ D-40a-H NO₂ D-40a-Me NO₂ C(O)OH NO₂ C(O)OCH₃ NO₂C(O)OEt NO₂ C(O)NH₂ NO₂ C(O)NHCH₂Pr-c NO₂ C(O)NHCH₂CF₃ NO₂C(O)N(CH₂OCH₃)CH₂CF₃ NO₂ C(O)N[C(O)CH₃]CH₂CF₃ NO₂ C(O)N[C(O)OCH₃]CH₂CF₃NO₂ C(O)NHCH₂CH═CH₂ NO₂ C(O)NHCH₂CH≡CH NO₂ C(O)NHCH₂CN NO₂C(O)NHCH₂OCH₂CF₃ NO₂ C(O)NHCH₂CH₂OCH₃ NO₂ C(O)NHCH₂CH₂OEt NO₂C(O)NHCH═NOCH₃ NO₂ C(O)NHCH═NOEt NO₂ C(O)NHCH₂CH═NOH NO₂C(O)NHCH₂CH═NOCH₃ NO₂ C(O)NHCH₂C(O)OH NO₂ C(O)NHCH₂C(O)OCH₃ NO₂C(O)NHCH₂C(O)NH₃ NO₂ C(O)NHCH₂C(O)NHCH₂CH₂Cl NO₂ C(O)NHCH₂C(O)NHCH₂CH₂BrNO₂ C(O)NHCH₂C(O)NHCH₂CF₃ NO₂ C(O)NHCH₂C(O)NHCH₂CH₂OH NO₂C(O)NHCH(CH₃)C(O)OH NO₂ C(O)NHCH(CH₃)C(O)OCH₃ NO₂C(O)NHCH(CH₃)C(O)NHCH₂CH₂Cl NO₂ C(O)NHCH(CH₃)C(O)NHCH₂CF₃ NO₂ C(O)NHPhNO₂ C(O)NH(Ph-4-F) NO₂ C(O)NH(Ph-4-CN) NO₂ C(O)NH(D-11a) NO₂C(O)NH(D-42a) NO₂ C(O)NH(D-42d)Cl NO₂ C(O)NH(D-43e)Cl NO₂ C(O)NH(D-45a)NO₂ C(O)N(CH₃)(D-45a) NO₂ C(O)N[C(O)CH₃](D-45a) NO₂C(O)N[C(O)OCH₃](D-45a) NO₂ C(O)NH(D-45c)Cl NO₂ C(O)N(CH₃)(D-45c)Cl NO₂C(O)N[C(O)CH₃](D-45c)Cl NO₂ C(O)N[C(O)OCH₃](D-45c)Cl NO₂ C(O)NH(D-46a)NO₂ C(O)NH(D-48a) NO₂ C(O)NH(E-1a) NO₂ C(O)NHCH₂(D-11a) NO₂C(O)NHCH₂(D-14a)CH₃ NO₂ C(O)NHCH₂(D-14b)Cl NO₂ C(O)NHCH₂(D-18a) NO₂C(O)NHCH₂(D-19a) NO₂ C(O)N[C(O)CH₃]CH₂(D-19a) NO₂C(O)N[C(O)Et]CH₂(D-19a) NO₂ C(O)N[C(O)OCH₃]CH₂(D-19a) NO₂C(O)NHCH₂(D-25a) NO₂ C(O)NHCH₂(D-27a) NO₂ C(O)NHCH₂(D-28a) NO₂C(O)NHCH₂(D-31a) NO₂ C(O)NHCH₂(D-34a) NO₂ C(O)NHCH₂(D-36a) NO₂C(O)NHCH₂(D-42a) NO₂ C(O)N(CH₂CN)CH₂(D-42a) NO₂ C(O)N(CH₂OCH₃)CH₂(D-42a)NO₂ C(O)N[C(O)CH₃]CH₂(D-42a) NO₂ C(O)N[C(O)Et]CH₂(D-42a) NO₂C(O)N[C(O)OCH₃]CH₂(D-42a) NO₂ C(O)NHCH₂(D-44a) NO₂ C(O)NHCH₂(D-45a) NO₂C(O)NHCH₂(D-46a) NO₂ C(O)NHCH₂(D-48a) NO₂ C(O)NHCH₂(E-1a) NO₂C(O)NHCH₂(E-3a) NO₂ C(O)NHCH₂(E-5a) NO₂ C(O)NHC(O)OCH₃ NO₂C(O)N(CH₃)C(O)OCH₃ NO₂ C(O)N(Et)C(O)OCH₃ NO₂ C(O)N(CH₂CN)C(O)OCH₃ NO₂C(O)N(CH₂OCH₃)C(O)OCH₃ NO₂ C(O)N[C(O)Et]C(O)OCH₃ NO₂C(O)N[C(O)Pr-n]C(O)OCH₃ NO₂ C(O)N[C(O)Pr-i]C(O)OCH₃ NO₂C(O)N[C(O)OCH₃]C(O)OCH₃ NO₂ C(O)NHC(O)OEt NO₂ C(O)N(CH₃)C(O)OEt NO₂C(O)N(Et)C(O)OEt NO₂ C(O)N(CH₂CN)C(O)OEt NO₂ C(O)N(CH₂OCH₃)C(O)OEt NO₂C(O)N[C(O)CH₃]C(O)OEt NO₂ C(O)N[C(O)Et]C(O)OEt NO₂C(O)N[C(O)Pr-n]C(O)OEt NO₂ C(O)N[C(O)Pr-i]C(O)OEt NO₂C(O)N[C(O)OCH₃]C(O)OEt NO₂ C(O)NHC(O)OPr-i NO₂ C(O)N(CH₃)C(O)OPr-i NO₂C(O)N(Et)C(O)OPr-i NO₂ C(O)N(CH₂CN)C(O)OPr-i NO₂ C(O)N(CH₂OCH₃)C(O)OPr-iNO₂ C(O)N[C(O)CH₃]C(O)OPr-i NO₂ C(O)N[C(O)Et]C(O)OPr-i NO₂C(O)N[C(O)Pr-n]C(O)OPr-i NO₂ C(O)N[C(O)Pr-i]C(O)OPr-i NO₂C(O)N[C(O)OCH₃]C(O)OPr-i NO₂ C(O)N[C(O)OEt]C(O)OPr-i NO₂ C(O)NHC(O)NH₂NO₂ C(O)NHN(CH₃)Ph NO₂ C(O)N[C(O)CH₃]N(CH₃)Ph NO₂C(O)N[C(O)OCH₃]N(CH₃)Ph NO₂ C(O)NHN(CH₃)(D-45a) NO₂C(O)N[C(O)CH₃]N(CH₃)(D-45a) NO₂ C(O)N[C(O)OCH₃]N(CH₃)(D-45a) NO₂ CH₂NHC(O)Pr-i NO₂ CH₂NH C(O)CF₃ NO₂ CH₂NH C(O)OEt NO₂ CH₂NH C(O)(Ph-2-CH₃)NO₂ CH₂NH C(O)NH(Ph-2-F) NO₂ CH₂N(CH₃)C(O)Me NO₂ CH₂N(i-Pr)C(O)Et NO₂CH(CH₃)NHC(O) CHF₂ NO₂ CH₂(T-1) CH₃ F CH₃ Cl CH₃ Br CH₃ I CH₃ CN CH₃ NO₂CH₃ NH₂ CH₃ NHC(O)CH₃ CH₃ NHC(O)OCH₃ CH₃ NHC(O)OEt CH₃ OH CH₃ OC(O)CH₃CH₃ OCH₂Ph CH₃ OSO₂CH₃ CH₃ OSO₂CF₃ CH₃ OSO₂Ph CH₃ OSO₂(Ph-4-CH₃) CH₃SCH₃ CH₃ S(O)CH₃ CH₃ SO₂CH₃ CH₃ SEt CH₃ S(O)Et CH₃ SO₂Et CH₃ SCH₂CF₃ CH₃SPh CH₃ SCH₂(D-42a) CH₃ D-38a CH₃ D-11a CH₃ D-21a CH₃ D-35a CH₃ D-36a-HCH₃ D-36a-Me CH₃ D-36b-Me CH₃ D-39a CH₃ D-40a-H CH₃ D-40a-Me CH₃ C(O)OHCH₃ C(O)OCH₃ CH₃ C(O)OEt CH₃ C(O)NH₂ CH₃ C(O)NHCH₃ CH₃ C(O)NHEt CH₃C(O)NHCH₂Pr-c CH₃ C(O)N(CH₃)CH₂Pr-c CH₃ C(O)N[C(O)CH₃]CH₂Pr-c CH₃C(O)N[C(O)OCH₃]CH₂Pr-c CH₃ C(O)NHCH₂CF₃ CH₃ C(O)N(CH₃)CH₂CF₃ CH₃C(O)N(Et)CH₂CF₃ CH₃ C(O)N(CH₂OCH₃)CH₂CF₃ CH₃ C(O)N[C(O)CH₃]CH₂CF₃ CH₃C(O)N[C(O)OCH₃]CH₂CF₃ CH₃ C(O)NHCH₂CH═CH₂ CH₃ C(O)NHCH₂CH≡CH CH₃C(O)NHCH₂OCH₂CF₃ CH₃ C(O)NHCH₂CH₂OCH₃ CH₃ C(O)NHCH₂CH₂OEt CH₃C(O)NHCH═NOCH₃ CH₃ C(O)NHC(CH₃)═NOCH₃ CH₃ C(O)NHCH═NOEt CH₃C(O)NHCH₂CH═NOH CH₃ C(O)NHCH₂CH═NOCH₃ CH₃ C(O)NHCH₂C(CH₃)═CNOCH₃ CH₃C(O)NHCH₂CN CH₃ C(O)NHCH(CN)OCH₂CF₃ CH₃ C(O)NHCH₂C(O)OH CH₃C(O)NHCH₂C(O)OCH₃ CH₃ C(O)NHCH₂C(O)OEt CH₃ C(O)NHCH₂C(O)OCH₂CF₃ CH₃C(O)NHCH₂C(O)NH₂ CH₃ C(O)NHCH₂C(O)NHCH₃ CH₃ C(O)NHCH₂C(O)N(CH₃)₂ CH₃C(O)NHCH₂C(O)NHEt CH₃ C(O)NHCH₂C(O)NHCH₂CH₂Cl CH₃C(O)NHCH₂C(O)N(CH₃)CH₂CH₂Cl CH₃ C(O)N(CH₃)CH₂C(O)NHCH₂CH₂Cl CH₃C(O)N[C(O)CH₃]CH₂C(O)NHCH₂CH₂Cl CH₃ C(O)N[C(O)OCH₃]CH₂C(O)NHCH₂CH₂Cl CH₃C(O)NHCH₂C(O)NHCH₂CH₂Br CH₃ C(O)NHCH₂C(O)NHCH₂CF₃ CH₃C(O)NHCH₂C(O)N(CH₃)CH₂CF₃ CH₃ C(O)N(CH₃)CH₂C(O)NHCH₂CF₃ CH₃C(O)N[C(O)CH₃]CH₂C(O)NHCH₂CF₃ CH₃ C(O)N[C(O)OCH₃]CH₂C(O)NHCH₂CF₃ CH₃C(O)NHCH₂C(O)NHCH₂CH₂OH CH₃ C(O)NHCH(CH₃)C(O)OH CH₃C(O)NHCH(CH₃)C(O)OCH₃ CH₃ C(O)NHCH(CH₃)C(O)NHCH₂CH₂Cl CH₃C(O)NHCH(CH₃)C(O)NHCH₂CF₃ CH₃ C(O)NHCH₂(E-1a) CH₃ C(O)NHCH₂(E-2a) CH₃C(O)NHCH₂(E-3a) CH₃ C(O)NHCH₂(E-5a) CH₃ C(O)NHCH₂(E-7a) CH₃ C(O)NHPh CH₃C(O)NH(Ph-4-F) CH₃ C(O)N(CH₃)(Ph-4-F) CH₃ C(O)N(Et)(Ph-4-F) CH₃C(O)N(CH₂CH═CH₂)(Ph-4-F) CH₃ C(O)N(CH₂CN)(Ph-4-F) CH₃C(O)N(CH₂OCH₃)(Ph-4-F) CH₃ C(O)N[C(O)CH₃](Ph-4-F) CH₃C(O)N[C(O)OCH₃](Ph-4-F) CH₃ C(O)NH(Ph-4-CN) CH₃ C(O)N(CH₃)(Ph-4-CN) CH₃C(O)N[C(O)CH₃](Ph-4-CN) CH₃ C(O)N[C(O)OCH₃](Ph-4-CN) CH₃C(O)NH(Ph-4-NO2) CH₃ C(O)NH(D-5a) CH₃ C(O)NH(D-5b)CH₃ CH₃C(O)NH(D-10b)CH₃ CH₃ C(O)NH(D-11a) CH₃ C(O)N(CH₃)(D-11a) CH₃C(O)N[C(O)CH₃](D-11a) CH₃ C(O)N[C(O)OCH₃](D-11a) CH₃ C(O)NH(D-12a)CH₃CH₃ C(O)NH(D-18a) CH₃ C(O)NH(D-32a) CH₃ C(O)NH(D-42a) CH₃C(O)N(CH₃)(D-42a) CH₃ C(O)N[C(O)CH₃](D-42a) CH₃ C(O)N[C(O)OCH₃](D-42a)CH₃ C(O)NH(D-42d)Cl CH₃ C(O)NH(D-43e)Cl CH₃ C(O)N(CH₃)(D-43e)Cl CH₃C(O)N[C(O)CH₃](D-43e)Cl CH₃ C(O)N[C(O)OCH₃](D-43e)Cl CH₃ C(O)NH(D-45a)CH₃ C(O)N(CH₃)(D-45a) CH₃ C(O)N[C(O)CH₃](D-45a) CH₃C(O)N[C(O)OCH₃](D-45a) CH₃ C(O)NH(D-45b)CH₃ CH₃ C(O)NH(D-45c)Cl CH₃C(O)N(CH₃)(D-45c)Cl CH₃ C(O)N[C(O)CH₃](D-45c)Cl CH₃C(O)N[C(O)OCH₃](D-45c)Cl CH₃ C(O)NH(D-45c)Br CH₃ C(O)N[C(O)CH₃](D-45c)BrCH₃ C(O)N[C(O)OCH₃](D-45c)Br CH₃ C(O)NH(D-46a) CH₃ C(O)NH(D-48a) CH₃C(O)NH(E-1a) CH₃ C(O)NHCH₂Ph CH₃ C(O)NHCH(CH₃)Ph CH₃ C(O)NHCH(CF₃)Ph CH₃C(O)NHCH(CN)Ph CH₃ C(O)NHCH₂(Ph-4-NO₂) CH₃ C(O)NHCH₂(D-8a) CH₃C(O)NHCH₂(D-11a) CH₃ C(O)NHCH(CN)(D-11a) CH₃ C(O)NHCH₂(D-12a)CH₃ CH₃C(O)NHCH₂(D-13b)Cl CH₃ C(O)NHCH₂(D-13c)Cl CH₃ C(O)NHCH₂(D-14a)CH₃ CH₃C(O)NHCH₂(D-14b)Cl CH₃ C(O)NHCH₂(D-18a) CH₃ C(O)NHCH₂(D-19a) CH₃C(O)N(CH₃)CH₂(D-19a) CH₃ C(O)N[C(O)CH₃]CH₂(D-19a) CH₃C(O)N[C(O)Et]CH₂(D-19a) CH₃ C(O)N[C(O)OCH₃)CH₂(D-19a) CH₃C(O)NHCH₂(D-20a) CH₃ C(O)NHCH₂(D-22a)CH₃ CH₃ C(O)NHCH₂(D-24a)CH₃ CH₃C(O)NHCH₂(D-25a) CH₃ C(O)NHCH₂(D-27a) CH₃ C(O)NHCH₂(D-28a) CH₃C(O)NHCH₂(D-31a) CH₃ C(O)NHCH₂(D-34a) CH₃ C(O)NHCH₂(D-36a) CH₃C(O)NHCH(CN)(D-36a) CH₃ C(O)NHCH₂(D-42a) CH₃ C(O)NHCH(CH₃)(D-42a) CH₃C(O)NHCH(CF₂)(D-42a) CH₃ C(O)NHCH(CN)(D-42a) CH₃ C(O)N(CH₃)CH₂(D-42a)CH₃ C(O)N(CH₂C≡CH)CH₂(D-42a) CH₃ C(O)N(CH₂CN)CH₂(D-42a) CH₃C(O)N(CH₂OCH₃)CH₂(D-42a) CH₃ C(O)N[C(O)CH₃]CH₂(D-42a) CH₃C(O)N[C(O)Et]CH₂(D-42a) CH₃ C(O)N[C(O)OCH₃]CH₂(D-42a) CH₃C(O)NHCH₂(D-44a) CH₃ C(O)NHCH₂(D-45a) CH₃ C(O)NHCH₂(D-46a) CH₃C(O)NHCH₂(D-48a) CH₃ C(O)NHC(O)OCH₃ CH₃ C(O)N(CH₃)C(O)OCH₃ CH₃C(O)N(Et)C(O)OCH₃ CH₃ C(O)N(CH₂CN)C(O)OCH₃ CH₃ C(O)N(CH₂OCH₃)C(O)OCH₃CH₃ C(O)N[C(O)CH₃]C(O)OCH₃ CH₃ C(O)N[C(O)Et]C(O)OCH₃ CH₃C(O)N[C(O)Pr-n]C(O)OCH₃ CH₃ C(O)N(C(O)Pr-i]C(O)OCH₃ CH₃C(O)N[C(O)OCH₃]C(O)OCH₃ CH₃ C(O)NHC(O)OEt CH₃ C(O)N(CH₃)C(O)OEt CH₃C(O)N(Et)C(O)OEt CH₃ C(O)N(CH₂CN)C(O)OEt CH₃ C(O)N(CH₂OCH₃)C(O)OEt CH₃C(O)N[C(O)CH₃]C(O)OEt CH₃ C(O)N[C(O)Et]C(O)OEt CH₃C(O)N[C(O)Pr-n]C(O)OEt CH₃ C(O)N[C(O)Pr-i]C(O)OEt CH₃C(O)N[C(O)OCH₃]C(O)OEt CH₃ C(O)NHC(O)OPr-i CH₃ C(O)N(CH₃)C(O)OPr-i CH₃C(O)N(Et)C(O)OPr-i CH₃ C(O)N(CH₂CN)C(O)OPr-i CH₃ C(O)N(CH₂OCH₃)C(O)OPr-iCH₃ C(O)N[C(O)CH₃]C(O)OPr-i CH₃ C(O)N[C(O)Et]C(O)OPr-i CH₃C(O)N[C(O)Pr-n]C(O)OPr-i CH₃ C(O)N[C(O)Pr-i]C(O)OPr-i CH₃C(O)N[C(O)OCH₃]C(O)OPr-i CH₃ C(O)N[C(O)OEt]C(O)OPr-i CH₃ C(O)NHC(O)NH₂CH₃ C(O)NHC(O)NHCH₃ CH₃ C(O)NHNH₂ CH₃ C(O)NHNHPh CH₃ C(O)NHN(CH₃)Ph CH₃C(O)N(CH₃)NHPh CH₃ C(O)N(CH₃)N(CH₃)Ph CH₃ C(O)N[C(O)CH₃]N(CH₃)Ph CH₃C(O)N[C(O)OCH₃]N(CH₃)Ph CH₃ C(O)NHNH(D-45a) CH₃ C(O)NHN(CH₃)(D-45a) CH₃C(O)N(CH₃)N(CH₃)(D-45a) CH₃ C(O)N[C(O)CH₃]N(CH₃)(D-45a) CH₃C(O)N[C(O)OCH₃]N(CH₃)(D-45a) CH₃ CH₂NH C(O)Pr-i CH₃ CH₂NH C(O)CF₃ CH₃CH₂NH C(O)OEt CH₃ CH₂NH C(O)(Ph-2-CH₃) CH₃ CH₂NH C(O)NH(Ph-2-F) CH₃CH₂N(CH₃)C(O)Me CH₃ CH₂N(i-Pr)C(O)Et CH₃ CH(CH₃)NHC(O) CHF₂ CH₃ CH₂(T-1)Et F Et Cl Et Br Et I Et NO₂ Et NH₂ Et NHC(O)CH₃ Et NHC(O)OCH₃ EtNHC(O)OEt Et OH Et OC(O)CH₃ Et OCH₂Ph Et OSO₂CH₃ Et OSO₂CF₃ Et OSO₂Ph EtOSO₂(Ph-4-CH₃) Et SCH₃ Et S(O)CH₃ Et SO₂CH₃ Et SEt Et S(O)Et Et SO₂Et EtSCH₂CF₃ Et SPh Et SCH₂(D-42a) Et D-38a Et D-11a Et D-21a Et D-35a EtD-36a-H Et D-36a-Me Et D-36b-Me Et D-39a Et D-40a-H Et D-40a-Me EtC(O)OH Et C(O)OCH₃ Et C(O)OEt Et C(O)NH₂ Et C(O)NHCH₂Pr-c EtC(O)NHCH₂CF₃ Et C(O)NHCH₂CH═CH₂ Et C(O)NHCH₂CH≡CH Et C(O)NHCH₂CN EtC(O)NHCH₂OCH₂CF₃ Et C(O)NHCH₂CH₂OCH₃ Et C(O)NHCH₂CH₂OEt EtC(O)NHCH═NOCH₃ Et C(O)NHCH═NOEt Et C(O)NHCH₂CH═NOH Et C(O)NHCH₂CH═NOCH₃Et C(O)NHCH₂C(O)OH Et C(O)NHCH₂C(O)OCH₃ Et C(O)NHCH₂C(O)OEt EtC(O)NHCH₂C(O)NH₂ Et C(O)NHCH₂C(O)NHCH₂CF₃ Et C(O)NHCH(CH₃)C(O)OH EtC(O)NHCH(CH₃)C(O)OCH₃ Et C(O)NHCH(CH₃)C(O)NHCH₂CF₃ Et C(O)NH(D-11a) EtC(O)NH(D-42a) Et C(O)NH(D-42d)Cl Et C(O)NH(D-43e)Cl Et C(O)NH(D-45a) EtC(O)N[C(O)CH₃](D-45a) Et C(O)N[C(O)OCH₃](D-45a) Et C(O)NH(D-45c)Cl EtC(O)N[C(O)CH₃](D-45c)Cl Et C(O)N[C(O)OCH₃](D-45c)Cl Et C(O)NH(D-46a) EtC(O)NH(D-48a) Et C(O)NH(E-1a) Et C(O)NHCH₂(D-11a) Et C(O)NHCH₂(D-14a)CH₃Et C(O)NHCH₂(D-14b)Cl Et C(O)NHCH₂(D-18a) Et C(O)NHCH₂(D-19a) EtC(O)N[C(O)CH₃]CH₂(D-19a) Et C(O)N[C(O)Et]CH₂(D-19a) EtC(O)N[C(O)OCH₃]CH₂(D-19a) Et C(O)NHCH₂(D-25a) Et C(O)NHCH₂(D-27a) EtC(O)NHCH₂(D-28a) Et C(O)NHCH₂(D-31a) Et C(O)NHCH₂(D-34a) EtC(O)NHCH₂(D-36a) Et C(O)NHCH₂(D-42a) Et C(O)N(CH₂OCH₃)CH₂(D-42a) EtC(O)N[C(O)CH₃]CH₂(D-42a) Et C(O)N[C(O)Et]CH₂(D-42a) EtC(O)N[C(O)OCH₃]CH₂(D-42a) Et C(O)NHCH₂(D-44a) Et C(O)NHCH₂(D-45a) EtC(O)NHCH₂(D-46a) Et C(O)NHCH₂(D-48a) Et C(O)NHCH₂(E-1a) EtC(O)NHCH₂(E-3a) Et C(O)NHCH₂(E-5a) Et C(O)NHC(O)OCH₃ EtC(O)N(CH₃)C(O)OCH₃ Et C(O)N(Et)C(O)OCH₃ Et C(O)N(CH₂OCH₃)C(O)OCH₃ EtC(O)N[C(O)Et]C(O)OCH₃ Et C(O)N[C(O)Pr-n]C(O)OCH₃ EtC(O)N[C(O)Pr-i]C(O)OCH₃ Et C(O)N[C(O)OCH₃]C(O)OCH₃ Et C(O)NHC(O)OEt EtC(O)N(CH₃)C(O)OEt Et C(O)N(Et)C(O)OEt Et C(O)N(CH₂OCH₃)C(O)OEt EtC(O)N[C(O)CH₃]C(O)OEt Et C(O)N[C(O)Et]C(O)OEt Et C(O)N[C(O)Pr-n]C(O)OEtEt C(O)N[C(O)Pr-i]C(O)OEt Et C(O)N[C(O)OCH₃]C(O)OEt Et C(O)NHC(O)OPr-iEt C(O)N(CH₃)C(O)OPr-i Et C(O)N(Et)C(O)OPr-i Et C(O)N(CH₂OCH₃)C(O)OPr-iEt C(O)N[C(O)CH₃]C(O)OPr-i Et C(O)N[C(O)Et]C(O)OPr-i EtC(O)N[C(O)Pr-n]C(O)OPr-i Et C(O)N[C(O)Pr-i]C(O)OPr-i EtC(O)N[C(O)OCH₃]C(O)OPr-i Et C(O)N[C(O)OEt]C(O)OPr-i Et C(O)NHC(O)NH₂ EtC(O)NHN(CH₃)Ph Et C(O)N[C(O)CH₃]N(CH₃)Ph Et C(O)N[C(O)OCH₃]N(CH₃)Ph EtC(O)NHN(CH₃)(D-45a) Et C(O)N[C(O)CH₃]N(CH₃)(D-45a) EtC(O)N[C(O)OCH₃]N(CH₃)(D-45a) Et CH₂NH C(O)Pr-i Et CH₂NH C(O)CF₃ Et CH₂NHC(O)OEt Et CH₂NH C(O)(Ph-2-CH₃) Et CH₂NH C(O)NH(Ph-2-F) EtCH₂N(CH₃)C(O)Me Et CH₂N(i-Pr)C(O)Et Et CH(CH₃)NHC(O) CHF₂ Et CH₂(T-1)CF₃ F CF₃ Cl CF₃ Br CF₃ I CF₃ NO₂ CF₃ NH₂ CF₃ NHC(O)CH₃ CF₃ NHC(O)OCH₃CF₃ NHC(O)OEt CF₃ OH CF₃ OC(O)CH₃ CF₃ OCH₂Ph CF₃ OSO₂CH₃ CF₃ OSO₂CF₃ CF₃OSO₂Ph CF₃ OSO₂(Ph-4-CH₃) CF₃ SCH₃ CF₃ S(O)CH₃ CF₃ SO₂CH₃ CF₃ SEt CF₃S(O)Et CF₃ SO₂Et CF₃ SCH₂CF₃ CF₃ SPh CF₃ SCH₂(D-42a) CF₃ D-38a CF₃ D-11aCF₃ D-21a CF₃ D-35a CF₃ D-36a-H CF₃ D-36a-Me CF₃ D-36b-Me CF₃ D-39a CF₃D-40a-H CF₃ D-40a-Me CF₃ C(O)OH CF₃ C(O)OCH₃ CF₃ C(O)OEt CF₃ C(O)NH₂ CF₃C(O)NHCH₂Pr-c CF₃ C(O)NHCH₂CF₃ CF₃ C(O)NHCH₂CH═CH₂ CF₃ C(O)NHCH₂CH≡CHCF₃ C(O)NHCH₂CN CF₃ C(O)NHCH₂OCH₂CF₃ CF₃ C(O)NHCH₂CH₂OCH₃ CF₃C(O)NHCH₂CH₂OEt CF₃ C(O)NHCH═NOCH₃ CF₃ C(O)NHCH═NOEt CF₃ C(O)NHCH₂CH═NOHCF₃ C(O)NHCH₂CH═NOCH₃ CF₃ C(O)NHCH₂C(O)OH CF₃ C(O)NHCH₂C(O)OCH₃ CF₃C(O)NHCH₂C(O)OEt CF₃ C(O)NHCH₂C(O)NH₂ CF₃ C(O)NHCH₂C(O)NHCH₂CF₃ CF₃C(O)NHCH(CH₃)C(O)OH CF₃ C(O)NHCH(CH₃)C(O)OCH₃ CF₃C(O)NHCH(CH₃)C(O)NHCH₂CF₃ CF₃ C(O)NH(D-11a) CF₃ C(O)NH(D-42a) CF₃C(O)NH(D-42d)Cl CF₃ C(O)NH(D-43e)Cl CF₃ C(O)NH(D-45a) CF₃C(O)N[C(O)CH₃](D-45a) CF₃ C(O)N[C(O)OCH₃](D-45a) CF₃ C(O)NH(D-45c)Cl CF₃C(O)N[C(O)CH₃](D-45c)Cl CF₃ C(O)N[C(O)OCH₃](D-45c)Cl CF₃ C(O)NH(D-46a)CF₃ C(O)NH(D-48a) CF₃ C(O)NH(E-1a) CF₃ C(O)NHCH₂(D-11a) CF₃C(O)NHCH₂(D-14a)CH₃ CF₃ C(O)NHCH₂(D-14b)Cl CF₃ C(O)NHCH₂(D-18a) CF₃C(O)NHCH₂(D-19a) CF₃ C(O)N[C(O)CH₃]CH₂(D-19a) CF₃C(O)N[C(O)Et]CH₂(D-19a) CF₃ C(O)N[C(O)OCH₃]CH₂(D-19a) CF₃C(O)NHCH₂(D-25a) CF₃ C(O)NHCH₂(D-27a) CF₃ C(O)NHCH₂(D-28a) CF₃C(O)NHCH₂(D-31a) CF₃ C(O)NHCH₂(D-34a) CF₃ C(O)NHCH₂(D-36a) CF₃C(O)NHCH₂(D-42a) CF₃ C(O)N[C(O)CH₃]CH₂(D-42a) CF₃C(O)N[C(O)Et]CH₂(D-42a) CF₃ C(O)N[C(O)OCH₃]CH₂(D-42a) CF₃C(O)NHCH₂(D-44a) CF₃ C(O)NHCH₂(D-45a) CF₃ C(O)NHCH₂(D-46a) CF₃C(O)NHCH₂(D-48a) CF₃ C(O)NHCH₂(E-1a) CF₃ C(O)NHCH₂(E-3a) CF₃C(O)NHCH₂(E-5a) CF₃ C(O)NHC(O)OCH₃ CF₃ C(O)N(CH₃)C(O)OCH₃ CF₃C(O)N(Et)C(O)OCH₃ CF₃ C(O)N(CH₂CN)C(O)OCH₃ CF₃ C(O)N(CH₂OCH₃)C(O)OCH₃CF₃ C(O)N[C(O)Et]C(O)OCH₃ CF₃ C(O)N[C(O)Pr-n]C(O)OCH₃ CF₃C(O)N[C(O)Pr-i]C(O)OCH₃ CF₃ C(O)N[C(O)OCH₃]C(O)OCH₃ CF₃ C(O)NHC(O)OEtCF₃ C(O)N(CH₃)C(O)OEt CF₃ C(O)N(Et)C(O)OEt CF₃ C(O)N(CH₂CN)C(O)OEt CF₃C(O)N(CH₂OCH₃)C(O)OEt CF₃ C(O)N[C(O)CH₃]C(O)OEt CF₃ C(O)N[C(O)Et]C(O)OEtCF₃ C(O)N[C(O)Pr-n]C(O)OEt CF₃ C(O)N[C(O)Pr-i]C(O)OEt CF₃C(O)N[C(O)OCH₃]C(O)OEt CF₃ C(O)NHC(O)OPr-i CF₃ C(O)N(CH₃)C(O)OPr-i CF₃C(O)N(Et)C(O)OPr-i CF₃ C(O)N(CH₂CN)C(O)OPr-i CF₃ C(O)N(CH₂OCH₃)C(O)OPr-iCF₃ C(O)N[C(O)CH₃]C(O)OPr-i CF₃ C(O)N[C(O)Et]C(O)OPr-i CF₃C(O)N[C(O)Pr-n]C(O)OPr-i CF₃ C(O)N[C(O)Pr-i]C(O)OPr-i CF₃C(O)N[C(O)OCH₃]C(O)OPr-i CF₃ C(O)N[C(O)OEt]C(O)OPr-i CF₃ C(O)NHC(O)NH₂CF₃ C(O)NHN(CH₃)Ph CF₃ C(O)N[C(O)CH₃]N(CH₃)Ph CF₃C(O)N[C(O)OCH₃]N(CH₃)Ph CF₃ C(O)NHN(CH₃)(D-45a) CF₃C(O)N[C(O)CH₃]N(CH₃)(D-45a) CF₃ C(O)N[C(O)OCH₃]N(CH₃)(D-45a) CF₃ CH₂NHC(O)Pr-i CF₃ CH₂NH C(O)CF₃ CF₃ CH₂NH C(O)OEt CF₃ CH₂NH C(O)(Ph-2-CH₃)CF₃ CH₂NH C(O)NH(Ph-2-F) CF₃ CH₂N(CH₃)C(O)Me CF₃ CH₂N(i-Pr)C(O)Et CF₃CH(CH₃)NHC(O) CHF₂ CF₃ CH₂(T-1) F CH₃ F Cl F Br F I F NO₂ F NH₂ FNHC(O)CH₃ F NHC(O)OCH₃ F NHC(O)OEt F OH F OC(O)CH₃ F OCH₂Ph F OSO₂CH₃ FOSO₂CF₃ F OSO₂Ph F OSO₂(Ph-4-CH₃) F SCH₃ F S(O)CH₃ F SO₂CH₃ F SEt FS(O)Et F SO₂Et F SCH₂CF₃ F SPh F SCH₂(D-42a) F D-38a F D-11a F D-21a FD-35a F D-36a-H F D-36a-Me F D-36b-Me F D-39a F D-40a-H F D-40a-Me FC(O)OH F C(O)OCH₃ F C(O)OEt F C(O)NH₂ F C(O)NHCH₂Pr-c F C(O)NHCH₂CF₃ FC(O)NHCH₂CH═CH₂ F C(O)NHCH₂CH≡CH F C(O)NHCH₂CN F C(O)NHCH₂OCH₂CF₃ FC(O)NHCH₂CH₂OCH₃ F C(O)NHCH₂CH₂OEt F C(O)NHCH═NOCH₃ F C(O)NHCH═NOEt FC(O)NHCH₂CH═NOH F C(O)NHCH₂CH═NOCH₃ F C(O)NHCH₂C(O)OH FC(O)NHCH₂C(O)OCH₃ F C(O)NHCH₂C(O)NHCH₂CF₃ F C(O)NHCH(CH₃)C(O)OH FC(O)NHCH(CH₃)C(O)OCH₃ F C(O)NHCH(CH₃)C(O)NHCH₂CF₃ F C(O)NH(D-11a) FC(O)NH(D-42a) F C(O)NH(D-42d)Cl F C(O)NH(D-43e)Cl F C(O)NH(D-45a) FC(O)N[C(O)CH₃](D-45a) F C(O)N[C(O)OCH₃](D-45a) F C(O)NH(D-45c)Cl FC(O)N[C(O)CH₃](D-45c)Cl F C(O)N[C(O)OCH₃](D-45c)Cl F C(O)NH(D-46a) FC(O)NH(D-48a) F C(O)NH(E-1a) F C(O)NHCH₂(D-11a) F C(O)NHCH₂(D-14a)CH₃ FC(O)NHCH₂(D-14b)Cl F C(O)NHCH₂(D-18a) F C(O)NHCH₂(D-19a) FC(O)N[C(O)CH₃]CH₂(D-19a) F C(O)N[C(O)Et]CH₂(D-19a) FC(O)N[C(O)OCH₃]CH₂(D-19a) F C(O)NHCH₂(D-25a) F C(O)NHCH₂(D-27a) FC(O)NHCH₂(D-28a) F C(O)NHCH₂(D-31a) F C(O)NHCH₂(D-34a) FC(O)NHCH₂(D-36a) F C(O)NHCH₂(D-42a) F C(O)N(CH₃)CH₂(D-42a) FC(O)N(CH₂CN)CH₂(D-42a) F C(O)N(CH₂OCH₃)CH₂(D-42a) FC(O)N[C(O)CH₃]CH₂(D-42a) F C(O)N[C(O)Et]CH₂(D-42a) FC(O)N[C(O)OCH₃]CH₂(D-42a) F C(O)NHCH₂(D-44a) F C(O)NHCH₂(D-45a) FC(O)NHCH₂(D-46a) F C(O)NHCH₂(D-48a) F C(O)NHCH₂(E-1a) F C(O)NHCH₂(E-3a)F C(O)NHCH₂(E-5a) F C(O)NHC(O)OCH₃ F C(O)N(CH₃)C(O)OCH₃ FC(O)N(Et)C(O)OCH₃ F C(O)N(CH₂CN)C(O)OCH₃ F C(O)N(CH₂OCH₃)C(O)OCH₃ FC(O)N[C(O)Et]C(O)OCH₃ F C(O)N[C(O)Pr-n]C(O)OCH₃ FC(O)N[C(O)Pr-i]C(O)OCH₃ F C(O)N[C(O)OCH₃]C(O)OCH₃ F C(O)NHC(O)OEt FC(O)N(CH₃)C(O)OEt F C(O)N(Et)C(O)OEt F C(O)N(CH₂CN)C(O)OEt FC(O)N(CH₂OCH₃)C(O)OEt F C(O)N[C(O)CH₃]C(O)OEt F C(O)N[C(O)Et]C(O)OEt FC(O)N[C(O)Pr-n]C(O)OEt F C(O)N[C(O)Pr-i]C(O)OEt F C(O)N[C(O)OCH₃]C(O)OEtF C(O)NHC(O)OPr-i F C(O)N(CH₃)C(O)OPr-i F C(O)N(Et)C(O)OPr-i FC(O)N(CH₂CN)C(O)OPr-i F C(O)N(CH₂OCH₃)C(O)OPr-i FC(O)N[C(O)CH₃]C(O)OPr-i F C(O)N[C(O)Et]C(O)OPr-i FC(O)N[C(O)Pr-n]C(O)OPr-i F C(O)N[C(O)Pr-i]C(O)OPr-i FC(O)N[C(O)OCH₃]C(O)OPr-i F C(O)N[C(O)OEt]C(O)OPr-i F C(O)NHN(CH₃)Ph FC(O)N[C(O)CH₃]N(CH₃)Ph F C(O)N[C(O)OCH₃]N(CH₃)Ph F C(O)NHN(CH₃)(D-45a) FC(O)N[C(O)CH₃]N(CH₃)(D-45a) F C(O)N[C(O)OCH₃]N(CH₃)(D-45a) F CH₂NHC(O)Pr-i F CH₂NH C(O)CF₃ F CH₂NH C(O)OEt F CH₂NH C(O)(Ph-2-CH₃) F CH₂NHC(O)NH(Ph-2-F) F CH₂N(CH₃)C(O)Me F CH₂N(i-Pr)(C(O)Et F CH(CH₃)NHC(O)CHF₂ F CH₂(T-1) Cl CH₃ Cl F Cl Br Cl I Cl NO₂ Cl NH₂ Cl NHC(O)CH₃ ClNHC(O)OCH₃ Cl NHC(O)OEt Cl OH Cl OC(O)CH₃ Cl OCH₂Ph Cl OSO₂CH₃ ClOSO₂CF₃ Cl OSO₂Ph Cl OSO₂(Ph-4-CH₃) Cl SCH₃ Cl S(O)CH₃ Cl SO₂CH₃ Cl SEtCl S(O)Et Cl SO₂Et Cl SCH₂CF₃ Cl SPh Cl SCH₂(D-42a) Cl D-38a Cl D-11a ClD-21a Cl D-35a Cl D-36a-H Cl D-36a-Me Cl D-36b-Me Cl D-39a Cl D-40a-H ClD-40a-Me Cl C(O)OH Cl C(O)OCH₃ Cl C(O)OEt Cl C(O)NH₂ Cl C(O)NHCH₂Pr-c ClC(O)NHCH₂CF₃ Cl C(O)N(CH₂OCH₃)CH₂CF₃ Cl C(O)N[C(O)CH₃]CH₂CF₃ ClC(O)N[C(O)OCH₃]CH₂CF₃ Cl C(O)NHCH₂CH═CH₂ Cl C(O)NHCH₂CH≡CH ClC(O)NHCH₂CN Cl C(O)NHCH₂OCH₂CF₃ Cl C(O)NHCH₂CH₂OCH₃ Cl C(O)NHCH₂CH₂OEtCl C(O)NHCH═NOCH₃ Cl C(O)NHCH═NOEt Cl C(O)NHCH₂CH═NOH ClC(O)NHCH₂CH═NOCH₃ Cl C(O)NHCH₂C(O)OH Cl C(O)NHCH₂C(O)OCH₃ ClC(O)NHCH₂C(O)NH₂ Cl C(O)NHCH₂C(O)NHCH₂CH₂Cl Cl C(O)NHCH₂C(O)NHCH₂CH₂BrCl C(O)NHCH₂C(O)NHCH₂CF₃ Cl C(O)NHCH₂C(O)NHCH₂CH₂OH ClC(O)NHCH(CH₃)C(O)OH Cl C(O)NHCH(CH₃)C(O)OCH₃ ClC(O)NHCH(CH₃)C(O)NHCH₂CH₂Cl Cl C(O)NHCH(CH₃)C(O)NHCH₂CF₃ ClC(O)NH(D-11a) Cl C(O)NH(D-42a) Cl C(O)NH(D-42d)Cl Cl C(O)NH(D-43e)Cl ClC(O)NH(D-45a) Cl C(O)N(CH₃)(D-45a) Cl C(O)N[C(O)CH₃](D-45a) ClC(O)N[C(O)OCH₃](D-45a) Cl C(O)NH(D-45c)Cl Cl C(O)N(CH₃)(D-45c)Cl ClC(O)N[C(O)CH₃](D-45c)Cl Cl C(O)N[C(O)OCH₃](D-45c)Cl Cl C(O)NH(D-46a) ClC(O)NH(D-48a) Cl C(O)NH(E-1a) Cl C(O)NHCH₂(D-11a) Cl C(O)NHCH₂(D-14a)CH₃Cl C(O)NHCH₂(D-14b)Cl Cl C(O)NHCH₂(D-18a) Cl C(O)NHCH₂(D-19a) ClC(O)N[C(O)CH₃]CH₂(D-19a) Cl C(O)N[C(O)Et]CH₂(D-19a) ClC(O)N[C(O)OCH₃]CH₂(D-19a) Cl C(O)NHCH₂(D-25a) Cl C(O)NHCH₂(D-27a) ClC(O)NHCH₂(D-28a) Cl C(O)NHCH₂(D-31a) Cl C(O)NHCH₂(D-34a) ClC(O)NHCH₂(D-36a) Cl C(O)NHCH₂(D-42a) Cl C(O)N(CH₂CN)CH₂(D-42a) ClC(O)N(CH₂OCH₃)CH₂(D-42a) Cl C(O)N[C(O)CH₃]CH₂(D-42a) ClC(O)N[C(O)Et]CH₂(D-42a) Cl C(O)N[C(O)OCH₃]CH₂(D-42a) Cl C(O)NHCH₂(D-44a)Cl C(O)NHCH₂(D-45a) Cl C(O)NHCH₂(D-46a) Cl C(O)NHCH₂(D-48a) ClC(O)NHCH₂(E-1a) Cl C(O)NHCH₂(E-3a) Cl C(O)NHCH₂(E-5a) Cl C(O)NHC(O)OCH₃Cl C(O)N(CH₃)C(O)OCH₃ Cl C(O)N(Et)C(O)OCH₃ Cl C(O)N(CH₂CN)C(O)OCH₃ ClC(O)N(CH₂OCH₃)C(O)OCH₃ Cl C(O)N[C(O)Et]C(O)OCH₃ ClC(O)N[C(O)Pr-n]C(O)OCH₃ Cl C(O)N[C(O)Pr-i]C(O)OCH₃ ClC(O)N[C(O)OCH₃]C(O)OCH₃ Cl C(O)NHC(O)OEt Cl C(O)N(CH₃)C(O)OEt ClC(O)N(Et)C(O)OEt Cl C(O)N(CH₂CN)C(O)OEt Cl C(O)N(CH₂OCH₃)C(O)OEt ClC(O)N[C(O)CH₃]C(O)OEt Cl C(O)N[C(O)Et]C(O)OEt Cl C(O)N[C(O)Pr-n]C(O)OEtCl C(O)N[C(O)Pr-i]C(O)OEt Cl C(O)N[C(O)OCH₃]C(O)OEt Cl C(O)NHC(O)OPr-iCl C(O)N(CH₃)C(O)OPr-i Cl C(O)N(Et)C(O)OPr-i Cl C(O)N(CH₂CN)C(O)OPr-i ClC(O)N(CH₂OCH₃)C(O)OPr-i Cl C(O)N[C(O)CH₃]C(O)OPr-i ClC(O)N[C(O)Et]C(O)OPr-i Cl C(O)N[C(O)Pr-n]C(O)OPr-i ClC(O)N[C(O)Pr-i]C(O)OPr-i Cl C(O)N[C(O)OCH₃]C(O)OPr-i ClC(O)N[C(O)OEt]C(O)OPr-i Cl C(O)NHC(O)NH₂ Cl C(O)NHN(CH₃)Ph ClC(O)N[C(O)CH₃]N(CH₃)Ph Cl C(O)N[C(O)OCH₃]N(CH₃)Ph Cl C(O)NHN(CH₃)(D-45a)Cl C(O)N[C(O)CH₃]N(CH₃)(D-45a) Cl C(O)N[C(O)OCH₃]N(CH₃)(D-45a) Cl CH₂NHC(O)Pr-i Cl CH₂NH C(O)CF₃ Cl CH₂NH C(O)OEt Cl CH₂NH C(O)(Ph-2-CH₃) ClCH₂NH C(O)NH(Ph-2-F) Cl CH₂N(CH₃)C(O)Me Cl CH₂N(i-Pr)C(O)Et ClCH(CH₃)NHC(O) CHF₂ Cl CH₂(T-1) Br CH₃ Br F Br I Br NO₂ Br NH₂ BrNHC(O)CH₃ Br NHC(O)OCH₃ Br NHC(O)OEt Br OH Br OC(O)CH₃ Br OCH₂Ph BrOSO₂CH₃ Br OSO₂CF₃ Br OSO₂Ph Br OSO₂(Ph-4-CH₃) Br SCH₃ Br S(O)CH₃ BrSO₂CH₃ Br SEt Br S(O)Et Br SO₂Et Br SCH₂CF₃ Br SPh Br SCH₂(D-42a) BrD-38a Br D-11a Br D-21a Br D-35a Br D-36a-H Br D-36a-Me Br D-36b-Me BrD-39a Br D-40a-H Br D-40a-Me Br C(O)OH Br C(O)OCH₃ Br C(O)OEt Br C(O)NH₂Br C(O)NHCH₂Pr-c Br C(O)NHCH₂CF₃ Br C(O)N(CH₂OCH₃)CH₂CF₃ BrC(O)N[C(O)CH₃]CH₂CF₃ Br C(O)N[C(O)OCH₃]CH₂CF₃ Br C(O)NHCH₂CH═CH₂ BrC(O)NHCH₂CH≡CH Br C(O)NHCH₂CN Br C(O)NHCH₂OCH₂CF₃ Br C(O)NHCH₂CH₂OCH₃ BrC(O)NHCH₂CH₂OEt Br C(O)NHCH═NOCH₃ Br C(O)NHCH═NOEt Br C(O)NHCH₂CH═NOH BrC(O)NHCH₂CH═NOCH₃ Br C(O)NHCH₂C(O)OH Br C(O)NHCH₂C(O)OCH₃ BrC(O)NHCH₂C(O)NH₂ Br C(O)NHCH₂C(O)NHCH₂CF₃ Br C(O)NHCH₂C(O)NHCH₂CH₂OH BrC(O)NHCH(CH₃)C(O)OH Br C(O)NHCH(CH₃)C(O)OCH₃ BrC(O)NHCH(CH₃)C(O)NHCH₂CF₃ Br C(O)NH(D-11a) Br C(O)NH(D-42a) BrC(O)NH(D-42d)Cl Br C(O)NH(D-43e)Cl Br C(O)NH(D-45a) Br C(O)N(CH₃)(D-45a)Br C(O)N[C(O)CH₃](D-45a) Br C(O)N[C(O)OCH₃](D-45a) Br C(O)NH(D-45c)Cl BrC(O)N(CH₃)(D-45c)Cl Br C(O)N[C(O)CH₃](D-45c)Cl BrC(O)N[C(O)OCH₃](D-45c)Cl Br C(O)NH(D-46a) Br C(O)NH(D-48a) BrC(O)NH(E-1a) Br C(O)NHCH₂(D-11a) Br C(O)NHCH₂(D-14a)CH₃ BrC(O)NHCH₂(D-14b)Cl Br C(O)NHCH₂(D-18a) Br C(O)NHCH₂(D-19a) BrC(O)N[C(O)CH₃]CH₂(D-19a) Br C(O)N[C(O)Et]CH₂(D-19a) BrC(O)N[C(O)OCH₃]CH₂(D-19a) Br C(O)NHCH₂(D-25a) Br C(O)NHCH₂(D-27a) BrC(O)NHCH₂(D-28a) Br C(O)NHCH₂(D-31a) Br C(O)NHCH₂(D-34a) BrC(O)NHCH₂(D-36a) Br C(O)NHCH₂(D-42a) Br C(O)N(CH₂CN)CH₂(D-42a) BrC(O)N(CH₂OCH₃)CH₂(D-42a) Br C(O)N[C(O)CH₃]CH₂ D-42a) BrC(O)N[C(O)Et]CH₂(D-42a) Br C(O)N[C(O)OCH₃]CH₂(D-42a) Br C(O)NHCH₂(D-44a)Br C(O)NHCH₂(D-45a) Br C(O)NHCH₂(D-46a) Br C(O)NHCH₂(D-48a) BrC(O)NHCH₂(E-1a) Br C(O)NHCH₂(E-3a) Br C(O)NHCH₂(E-5a) Br C(O)NHC(O)OCH₃Br C(O)N(CH₃)C(O)OCH₃ Br C(O)N(Et)C(O)OCH₃ Br C(O)N(CH₂CN)C(O)OCH₃ BrC(O)N(CH₂OCH₃)C(O)OCH₃ Br C(O)N[C(O)Et]C(O)OCH₃ BrC(O)N[C(O)Pr-n]C(O)OCH₃ Br C(O)N[C(O)Pr-i]C(O)OCH₃ BrC(O)N[C(O)OCH₃]C(O)OCH₃ Br C(O)NHC(O)OEt Br C(O)N(CH₃)C(O)OEt BrC(O)N(Et)C(O)OEt Br C(O)N(CH₂CN)C(O)OEt Br C(O)N(CH₂OCH₃)C(O)OEt BrC(O)N[C(O)CH₃]C(O)OEt Br C(O)N[C(O)Et]C(O)OEt Br C(O)N[C(O)Pr-n]C(O)OEtBr C(O)N[C(O)Pr-i]C(O)OEt Br C(O)N[C(O)OCH₃]C(O)OEt Br C(O)NHC(O)OPr-iBr C(O)N(CH₃)C(O)OPr-i Br C(O)N(Et)C(O)OPr-i Br C(O)N(CH₂CN)C(O)OPr-i BrC(O)N(CH₂OCH₃)C(O)OPr-i Br C(O)N[C(O)CH₃]C(O)OPr-i BrC(O)N[C(O)Et]C(O)OPr-i Br C(O)N[C(O)Pr-n]C(O)OPr-i BrC(O)N[C(O)Pr-i]C(O)OPr-i Br C(O)N[C(O)OCH₃]C(O)OPr-i BrC(O)N[C(O)OEt]C(O)OPr-i Br C(O)NHC(O)NH₂ Br C(O)NHN(CH₃)Ph BrC(O)N[C(O)CH₃]N(CH₃)Ph Br C(O)N[C(O)OCH₃]N(CH₃)Ph Br C(O)NHN(CH₃)(D-45a)Br C(O)N[C(O)CH₃]N(CH₃)(D-45a) Br C(O)N[C(O)OCH₃]N(CH₃)(D-45a) Br CH₂NHC(O)Pr-i Br CH₂NH C(O)CF₃ Br CH₂NH C(O)OEt Br CH₂NH C(O)(Ph-2-CH₃) BrCH₂NH C(O)NH(Ph-2-F) Br CH₂N(CH₃)C(O)Me Br CH₂N(i-Pr)C(O)Et BrCH(CH₃)NHC(O) CHF₂ Br CH₂(T-1) I CH₃ I NO₂ I NH₂ I NHC(O)CH₃ INHC(O)OCH₃ I NHC(O)OEt I OH I OC(O)CH₃ I OCH₂Ph I OSO₂CF₃ I SCH₃ IS(O)CH₃ I SO₂CH₃ I SEt I S(O)Et I SO₂Et I SCH₂CF₃ I SPh I SCH₂(D-42a) ID-38a I D-11a I D-21a I D-35a I D-36a-H I D-36a-Me I D-36b-Me I D-39a ID-40a-H I D-40a-Me I C(O)OH I C(O)OCH₃ I C(O)OEt I C(O)NH₂ IC(O)NHCH₂Pr-c I C(O)NHCH₂CF₃ I C(O)NHCH₂CH═CH₂ I C(O)NHCH₂CH≡CH IC(O)NHCH₂CN I C(O)NHCH₂OCH₂CF₃ I C(O)NHCH₂CH₂OCH₃ I C(O)NHCH₂CH₂OEt IC(O)NHCH═NOCH₃ I C(O)NHCH═NOEt I C(O)NHCH₂CH═NOH I C(O)NHCH₂CH═NOCH₃ IC(O)NHCH₂C(O)OH I C(O)NHCH₂C(O)OCH₃ I C(O)NHCH₂C(O)NHCH₂CF₃ IC(O)NHCH(CH₃)C(O)OH I C(O)NHCH(CH₃)C(O)OCH₃ I C(O)NHCH(CH₃)C(O)NHCH₂CF₃I C(O)NH(D-11a) I C(O)NH(D-42a) I C(O)NH(D-42d)Cl I C(O)NH(D-43e)Cl IC(O)NH(D-45a) I C(O)N[C(O)CH₃](D-45a) I C(O)N[C(O)OCH₃](D-45a) IC(O)NH(D-45c)Cl I C(O)N[C(O)CH₃](D-45c)Cl I C(O)N[C(O)OCH₃](D-45c)Cl IC(O)NH(D-46a) I C(O)NH(D-48a) I C(O)NH(E-1a) I C(O)NHCH₂(D-11a) IC(O)NHCH₂(D-14a)CH₃ I C(O)NHCH₂(D-14b)Cl I C(O)NHCH₂(D-18a) IC(O)NHCH₂(D-19a) I C(O)N[C(O)CH₃]CH₂(D-19a) I C(O)N[C(O)Et]CH₂(D-19a) IC(O)N[C(O)OCH₃]CH₂(D-19a) I C(O)NHCH₂(D-25a) I C(O)NHCH₂(D-27a) IC(O)NHCH₂(D-28a) I C(O)NHCH₂(D-31a) I C(O)NHCH₂(D-34a) IC(O)NHCH₂(D-36a) I C(O)NHCH₂(D-42a) I C(O)N(CH₂CN)CH₂(D-42a) IC(O)N(CH₂OCH₃)CH₂(D-42a) I C(O)N[C(O)CH₃]CH₂(D-42a) IC(O)N[C(O)Et]CH₂(D-42a) I C(O)N[C(O)OCH₃]CH₂(D-42a) I C(O)NHCH₂(D-44a) IC(O)NHCH₂(D-45a) I C(O)NHCH₂(D-46a) I C(O)NHCH₂(D-48a) I C(O)NHCH₂(E-1a)I C(O)NHCH₂(E-3a) I C(O)NHCH₂(E-5a) I C(O)NHC(O)OCH₃ IC(O)N(CH₃)C(O)OCH₃ I C(O)N(Et)C(O)OCH₃ I C(O)N(CH₂CN)C(O)OCH₃ IC(O)N(CH₂OCH₃)C(O)OCH₃ I C(O)N[C(O)Et]C(O)OCH₃ I C(O)N[C(O)Pr-n]C(O)OCH₃I C(O)N[C(O)Pr-i]C(O)OCH₃ I C(O)N[C(O)OCH₃]C(O)OCH₃ I C(O)NHC(O)OEt IC(O)N(CH₃)C(O)OEt I C(O)N(Et)C(O)OEt I C(O)N(CH₂CN)C(O)OEt IC(O)N(CH₂OCH₃)C(O)OEt I C(O)N[C(O)CH₃]C(O)OEt I C(O)N[C(O)Et]C(O)OEt IC(O)N[C(O)Pr-n]C(O)OEt I C(O)N[C(O)Pr-i]C(O)OEt I C(O)N[C(O)OCH₃]C(O)OEtI C(O)NHC(O)OPr-i I C(O)N(CH₃)C(O)OPr-i I C(O)N(Et)C(O)OPr-i IC(O)N(CH₂CN)C(O)OPr-i I C(O)N(CH₂OCH₃)C(O)OPr-i IC(O)N[C(O)CH₃]C(O)OPr-i I C(O)N[C(O)Et]C(O)OPr-i IC(O)N[C(O)Pr-n]C(O)OPr-i I C(O)N[C(O)Pr-i]C(O)OPr-i IC(O)N[C(O)OCH₃]C(O)OPr-i I C(O)N[C(O)OEt]C(O)OPr-i I C(O)NHC(O)NH₂ IC(O)NHN(CH₃)Ph I C(O)N[C(O)CH₃]N(CH₃)Ph I C(O)N[C(O)OCH₃]N(CH₃)Ph IC(O)NHN(CH₃)(D-45a) I C(O)N[C(O)CH₃]N(CH₃)(D-45a) IC(O)N[C(O)OCH₃]N(CH₃)(D-45a) I CH₂NH C(O)Pr-i I CH₂NH C(O)CF₃ I CH₂NHC(O)OEt I CH₂NH C(O)(Ph-2-CH₃) I CH₂NH C(O)NH(Ph-2-F) I CH₂N(CH₃)C(O)MeI CH₂N(i-Pr)C(O)Et I CH(CH₃)NHC(O) CHF₂ I CH₂(T-1) CN F CN Cl CN Br CN ICN NO₂ CN NH₂ CN NHC(O)CH₃ CN NHC(O)OCH₃ CN NHC(O)OEt CN OH CN OC(O)CH₃CN OCH₂Ph CN OSO₂CH₃ CN OSO₂CF₃ CN OSO₂Ph CN OSO₂(Ph-4-CH₃) CN SCH₃ CNS(O)CH₃ CN SO₂CH₃ CN SEt CN S(O)Et CN SO₂Et CN SCH₂CF₃ CN SPh CNSCH₂(D-42a) CN D-38a CN D-11a CN D-21a CN D-35a CN D-36a-H CN D-36a-MeCN D-36b-Me CN D-39a CN D-40a-H CN D-40a-Me CN C(O)OH CN C(O)OCH₃ CNC(O)OEt CN C(O)NH₂ CN C(O)NHCH₂Pr-c CN C(O)NHCH₂CF₃ CN C(O)NHCH₂CH═CH₂CN C(O)NHCH₂CH≡CH CN C(O)NHCH₂CN CN C(O)NHCH₂OCH₂CF₃ CN C(O)NHCH₂CH₂OCH₃CN C(O)NHCH₂CH₂OEt CN C(O)NHCH═NOCH₃ CN C(O)NHCH═NOEt CN C(O)NHCH₂CH═NOHCN C(O)NHCH₂CH═NOCH₃ CN C(O)NHCH₂C(O)OH CN C(O)NHCH₂C(O)OCH₃ CNC(O)NHCH₂C(O)OEt CN C(O)NHCH₂C(O)NH₂ CN C(O)NHCH₂C(O)NHCH₂CF₃ CNC(O)NHCH(CH₃)C(O)OH CN C(O)NHCH(CH₃)C(O)OCH₃ CNC(O)NHCH(CH₃)C(O)NHCH₂CF₃ CN C(O)NH(D-11a) CN C(O)NH(D-42a) CNC(O)NH(D-42d)Cl CN C(O)NH(D-43e)Cl CN C(O)NH(D-45a) CNC(O)N[C(O)CH₃](D-45a) CN C(O)N[C(O)OCH₃](D-45a) CN C(O)NH(D-45c)Cl CNC(O)N[C(O)CH₃](D-45c)Cl CN C(O)N[C(O)OCH₃](D-45c)Cl CN C(O)NH(D-46a) CNC(O)NH(D-48a) CN C(O)NH(E-1a) CN C(O)NHCH₂(D-11a) CN C(O)NHCH₂(D-14a)CH₃CN C(O)NHCH₂(D-14b)Cl CN C(O)NHCH₂(D-18a) CN C(O)NHCH₂(D-19a) CNC(O)N[C(O)CH₃]CH₂(D-19a) CN C(O)N[C(O)Et]CH₂(D-19a) CNC(O)N[C(O)OCH₃]CH₂(D-19a) CN C(O)NHCH₂(D-25a) CN C(O)NHCH₂(D-27a) CNC(O)NHCH₂(D-28a) CN C(O)NHCH₂(D-31a) CN C(O)NHCH₂(D-34a) CNC(O)NHCH₂(D-36a) CN C(O)NHCH₂(D-42a) CN C(O)N(CH₂OCH₃)CH₂(D-42a) CNC(O)N[C(O)CH₃]CH₂(D-42a) CN C(O)N[C(O)Et]CH₂(D-42a) CNC(O)N[C(O)OCH₃]CH₂(D-42a) CN C(O)NHCH₂(D-44a) CN C(O)NHCH₂(D-45a) CNC(O)NHCH₂(D-46a) CN C(O)NHCH₂(D-48a) CN C(O)NHCH₂(E-1a) CNC(O)NHCH₂(E-3a) CN C(O)NHCH₂(E-5a) CN C(O)NHC(O)OCH₃ CNC(O)N(CH₃)C(O)OCH₃ CN C(O)N(Et)C(O)OCH₃ CN C(O)N(CH₂OCH₃)C(O)OCH₃ CNC(O)N[C(O)Et]C(O)OCH₃ CN C(O)N[C(O)Pr-n]C(O)OCH₃ CNC(O)N[C(O)Pr-i]C(O)OCH₃ CN C(O)N[C(O)OCH₃]C(O)OCH₃ CN C(O)NHC(O)OEt CNC(O)N(CH₃)C(O)OEt CN C(O)N(Et)C(O)OEt CN C(O)N(CH₂OCH₃)C(O)OEt CNC(O)N[C(O)CH₃]C(O)OEt CN C(O)N[C(O)Et]C(O)OEt CN C(O)N[C(O)Pr-n]C(O)OEtCN C(O)N[C(O)Pr-i]C(O)OEt CN C(O)N[C(O)OCH₃]C(O)OEt CN C(O)NHC(O)OPr-iCN C(O)N(CH₃)C(O)OPr-i CN C(O)N(Et)C(O)OPr-i CN C(O)N(CH₂OCH₃)C(O)OPr-iCN C(O)N[C(O)CH₃]C(O)OPr-i CN C(O)N[C(O)Et]C(O)OPr-i CNC(O)N[C(O)Pr-n]C(O)OPr-i CN C(O)N[C(O)Pr-i]C(O)OPr-i CNC(O)N[C(O)OCH₃]C(O)OPr-i CN C(O)N[C(O)OEt]C(O)OPr-i CN C(O)NHC(O)NH₂ CNC(O)NHN(CH₃)Ph CN C(O)N[C(O)CH₃]N(CH₃)Ph CN C(O)N[C(O)OCH₃]N(CH₃)Ph CNC(O)NHN(CH₃)(D-45a) CN C(O)N[C(O)CH₃]N(CH₃)(D-45a) CNC(O)N[C(O)OCH₃]N(CH₃)(D-45a) CN CH₂NH C(O)Pr-i CN CH₂NH C(O)CF₃ CN CH₂NHC(O)OEt CN CH₂NH C(O)(Ph-2-CH₃) CN CH₂NH C(O)NH(Ph-2-F) CNCH₂N(CH₃)C(O)Me CN CH₂N(i-Pr)C(O)Et CN CH(CH₃)NHC(O) CHF₂ CN CH₂(T-1)

Specific examples of α,β-unsaturated carbonyl compounds represented byFormula (2) include, besides the above described compounds,3-penten-2-one, phorone, isophorone, diisopropylidene acetone,benzalacetone, 4-(2-furyl)-3-buten-2-one, 1,3-diphenyl-2-propen-1-one,1-phenyl-3-(3-nitrophenyl)-2-propen-1-one,1-(3-chlorophenyl)-3-(4-nitrophenyl)-2-propen-1-one,1-phenyl-3-(p-biphenyl)-2-propen-1-one,1-(naphthalen-2-yl)-3-phenyl-2-propen-1-one,3-(4-(methylsulfonyl)phenyl)-1-phenyl-2-propen-1-one,4-(3-oxo-3-phenyl-1-propen-1-yl) benzonitrile,1-(3-fluorophenyl)-3-(furan-2-yl)-2-propen-1-one and methyl4-(3-oxo-3-phenyl-1-propen-1-yl) benzoate.

EXAMPLES

Examples according to the present invention will be shown below.However, the present invention is not limited to these examples.

Synthesis Example Synthesis Example of Raw Material 1 Synthesis of3′,5′-dichloro-2,2,2-trifluoroacetophenone

Step 1: Synthesis of methyl 3,5-dichlorobenzoate

10 g of concentrated sulfuric acid was added to a methanol (120 g)solution of 50 g of 3,5-dichlorobenzoic acid, and the mixture wasrefluxed by heating for 5 hours. After cooling the reaction solution toroom temperature, the solvent was distilled off under reduced pressure.The obtained residue was dissolved into 200 g of ethyl acetate, washedwith water (200 g×2), then washed with a saturated aqueous solution ofsodium bicarbonate, and further washed with water. After drying theorganic phase over anhydrous magnesium sulfate, 48.6 g of the targetproduct was obtained as a white solid by removing the solvent bydistilling under reduced pressure.

¹H-NMR (CDCl₃, Me₄Si, 300 MHz) δ 7.90 (s, 2H), 7.54 (s, 1H), 3.94 (s,3H).

Step 2: Synthesis of 3′,5′-dichloro-2,2,2-trifluoroacetophenone

After adding 0.37 g of cesium fluoride to dimethoxyethane (300 g)solution of 25 g of methyl 3,5-dichlorobenzoate and 22.5 g oftrifluoromethyltrimethylsilane under ice cooling, the mixture was warmedto room temperature and stirred for 4 hours. After confirmingdisappearance of the raw materials, 200 g of water was added to thereaction solution, and the mixture was extracted with 200 g of ethylacetate. After dehydration/drying of the organic phase with saturatedsaline and then over anhydrous magnesium sulfate in this order, thesolvent was distilled off under reduced pressure to obtain 35.5 g of1-(3,5-dichlorophenyl)-2,2,2-trifluoro-1-trimethylsilyloxy-1-methoxyethaneas crude yellow liquid. The obtained crude product was dissolved into100 ml of tetrahydrofuran, and 9.75 ml of 1 M tetrahydrofuran (100 ml)solution of tetrabutylammonium fluoride was added in dropwise at roomtemperature. The mixture was stirred for 2 hours at the sametemperature. After completion of the reaction, the solvent was distilledoff under reduced pressure and the obtained residue was dissolved intoethyl acetate. After washing the organic phase with water and dryingover anhydrous magnesium sulfate, the solvent was distilled off underreduced pressure. 24.2 g of the target product as colorless liquid wasobtained by purifying the obtained residue by distilling under reducedpressure.

Boiling point 87° C. (1.7 kPa) ¹H-NMR (CDCl₃, Me₄Si, 300 MHz) δ7.92-7.93 (m, 2H), 7.70-7.71 (m, 1H).

Synthesis Example of Raw Material 2 Synthesis of4-acetyl-2-methylbenzoic Acid

Step 1: Synthesis of 4-acetyl-2-methylaniline

41.2 g (398 mmol) of 95% sulfuric acid was added in dropwise to asuspension solution of 38.1 g (199 mmol) of4′-acetyl-2′-methylacetanilide and 267 g of water at room temperature.After adding in dropwise, the mixture was heated to 85° C. and stirredfor 5 hours. After completion of the reaction, the sulfuric acidsolution cooled to room temperature was analyzed by a quantitativeanalysis method using HPLC. A content of 4-acetyl-2-methylaniline was27.0 g (yield 91%).

Step 2: Synthesis of 4′-bromo-3′-methylacetophenone

27.0 g of acetonitrile was added to a sulfuric acid solution of 27.0 g(181 mmol) of 4-acetyl-2-methylaniline, and the mixture was cooled to 0°C. An aqueous solution in which 13.1 g (190 mmol) of sodium nitrite wasdissolved into 26.2 g of water was added in dropwise to the mixture.After reacting the resultant mixture for 1 hour at 0° C., an aqueoussolution in which 1.1 g (18 mmol) of urea was dissolved into 2.2 g ofwater was added in dropwise, and the mixture was further stirred for 30minutes to obtain an aqueous solution of4-acetyl-2-methylbenzenediazonium sulfate. 5.18 g (36 mmol) of copperbromide, 62.2 g (362 mmol) of 47% hydrobromic acid and 81.0 g ofacetonitrile were fed into another reactor. The aqueous solution of4-acetyl-2-methylbenzenediazonium sulfate was added to this mixture indropwise over 1 hour with stirring at 50° C. After adding in dropwise,the mixture was reacted for 1 hour at 50° C. Then, 81 g of toluene wasadded and the mixture was stirred for 30 minutes, and the water phasewas separated. 54 g of toluene was added to the water phase andextracted again. The combined toluene solution was washed twice with 54g of 14% aqueous ammonia and once with 54 g of water to obtain a toluenesolution of 4′-bromo-3′-methylacetophenone. After removing the solventby distilling under reduced pressure, the residue was distilled underreduced pressure of 1.5 kPa. 32.8 g of the obtained fraction which wascollected in the range of outflow gas temperature from 130° C. to 137°C. was analyzed by HPLC. A percentage of relative area of4′-bromo-3′-methylacetophenone was 99.1% (yield 84%).

Step 3: Synthesis of 4-acetyl-2-methylbenzoic Acid

63.9 g (300 mmol) of 4′-bromo-3′-methylacetophenone, 256 g of toluene,32 g of water, 45.5 g (330 mmol) of potassium carbonate, 9.66 g (30mmol) of tetra(n-butyl) ammonium bromide, 1.45 g (water content 55.95%by weight) of activated charcoal supported 5% palladium and 0.372 g(0.90 mmol) of 1,3-bis(diphenylphosphino)propane were fed into apressure-tight reactor, and reaction was performed at 120° for 7 hoursby pressurizing with carbon monoxide at 0.8 MPa. After cooling thereaction solution to room temperature, inside of the reactor was purgedwith nitrogen, and then the pressure was reduced to atmosphere pressure.224 g of water was added, and stirred for 30 minutes. Catalyst wasfiltered with Celite and the organic phase was separated. 43.8 g (420mmol) of 35% hydrochloric acid was added to the water phase. Theobtained slurry was filtered, and then dried under reduced pressure toobtain 48.1 g of 4-acetyl-2-methylbenzoic acid as white crystal (yield90%).

Synthesis Example of Raw Material 2-2 Synthesis of4-acetyl-2-methylbenzoic Acid (2nd Method)

16.6 g (120 mmol) of potassium carbonate, 30.1 g (300 mmol) of n-butylvinyl ether, 44.9 mg (0.2 mmol) of palladium acetate and 0.247 g (0.6mmol) of 1,3-bis(diphenylphosphino)propane were added to a suspensionsolution of 21.5 g (100 mmol) of 4-bromo-2-methylbenzoic acid and 64.5 gof n-butanol. After degassing and nitrogen-purging inside of thereactor, the mixture was refluxed for 5 hours. After cooling thereaction solution to 80° C., n-butanol and n-butyl vinyl ether weredistilled off under reduced pressure. After adding 172 g of toluene and108 g of water, the mixture was neutralized by adding 15.6 g (150 mmol)of concentrated hydrochloric acid, and the water phase was separated.The obtained toluene solution was analyzed by a quantitative analysismethod using HPLC. A content of 4-acetyl-2-methylbenzoic acid was 16.9 g(yield 95%).

Synthesis Example of Raw Material 3 Synthesis of4-acetyl-2-methylbenzoic Acid Amide

Step 1: Synthesis of 4-acetyl-2-methylbenzyl Chloride

28 ml of dichloromethane, 4 ml of oxalyl chloride, and a drop ofN,N-dimethylformamide were added to 5.0 g of 4-acetyl-2-methylbenzoicacid, and the mixture was stirred for 3 hours at room temperature. Afterremoving the solvent by distilling under reduced pressure, 5.6 g ofcrude 4-acetyl-2-methylbenzyl chloride was obtained.

¹H-NMR (CDCl₃, Me₄Si, 400 MHz) δ 8.26 (d, J=8.2 Hz, 1H), 7.82-7.91 (m,2H), 2.65 (s, 3H), 2.63 (s, 3H).

Step 2: Synthesis of 4-acetyl-2-methylbenzoic Acid Amide

21 ml of dichloromethane was added to 2 g of concentrated aqueousammonia, and the mixture was cooled with ice. A dichloromethane (3 ml)solution of 1.39 g of crude 4-acetyl-2-methylbenzyl chloride was addedslowly to the mixture, and stirred for 2 hours with ice cooling. 24 mlof tetrahydrofuran was added to the reaction solution, and furtherstirred for 2 hours at room temperature. Then, large part of the solventwas distilled off under reduced pressure, and the slurry-state reactionsolution was filtered. The obtained solid was washed with water andtoluene. The solid was dried under reduced pressure to obtain 1.03 g of4-acetyl-2-methylbenzoic acid amide.

¹H-NMR (CDCl₃, Me₄Si, 400 MHz) δ 7.76-7.84 (m, 2H), 7.53 (d, J=7.9 Hz,1H), 5.87 (br s, 1H), 5.81 (br s, 1H), 2.56 (s, 3H), 2.55 (s, 3H).Melting point 152-154° C.

Example 1-1 Synthesis of1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-oneExample 1-1-1

2.13 g of 4-bromo-3-methylacetophenone which can be synthesized inaccordance with the method described in WO 96/19477 pamphlet, 2.43 g of3′,5′-dichloro-2,2,2-trifluoroacetophenone, 4.86 g of n-heptane and 0.20g of triethylamine were fed and the mixture was stirred for 14 hours at60° C. The solid generated in the reaction solution was collected byfiltration under reduced pressure, and the solid was washed with 1 ml ofn-heptane. 4.15 g of1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-oneas a white solid was obtained by drying under reduced pressure.

Example 1-1-2

6.39 g of 4-bromo-3-methylacetophenone, 7.29 g of3′,5′-dichloro-2,2,2-trifluoroacetophenone, 19.2 g of n-heptane and 5.56g of tributylamine were fed and the mixture was stirred for 9 hours at60° C. The solid generated in the reaction solution was collected byfiltration under reduced pressure, and the solid was washed with 6.4 gof n-heptane. 10.9 g of1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-oneas a white solid was obtained by drying under reduced pressure.

Example 1-1-3

0.26 g of 4-bromo-3-methylacetophenone, 0.30 g of3′,5′-dichloro-2,2,2-trifluoroacetophenone, 0.75 g of chlorobenzene and0.22 g of tributylamine were fed and the mixture was stirred for 96hours at room temperature. The solid generated in the reaction solutionwas collected by filtration under reduced pressure. 0.43 g of1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-oneas a white solid was obtained by drying under reduced pressure.

Example 1-1-4

5.33 g of 4-bromo-3-methylacetophenone, 6.08 g of3′,5′-dichloro-2,2,2-trifluoroacetophenone, 6.08 g of toluene and 1.39 gof tributylamine were fed and the mixture was stirred for 13 hours at60° C. The solid generated in the reaction solution was collected byfiltration under reduced pressure. 10.16 g of1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-oneas a white solid was obtained by drying under reduced pressure.

Example 1-1-5

1.07 g of 4-bromo-3-methylacetophenone, 1.22 g of3′,5′-dichloro-2,2,2-trifluoroacetophenone and 5.0 g of tributylaminewere fed and the mixture was stirred for 21 hours at room temperature.The solid generated in the reaction solution was collected by filtrationunder reduced pressure, and the solid was washed with 1.5 ml ofn-heptane. 2.01 g of1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-oneas a white solid was obtained by drying under reduced pressure.

Example 1-1-6

1.07 g of 4-bromo-3-methylacetophenone, 1.22 g of3′,5′-dichloro-2,2,2-trifluoroacetophenone, 3.66 g of distilled water,0.14 g of potassium carbonate and 33 mg of sodium laurate were fed andthe mixture was stirred for 12 hours at 70° C. The solid generated inthe reaction solution was collected by filtration under reducedpressure, and the solid was washed with 2 ml of distilled water. 2.10 gof1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-oneas a white solid was obtained by drying under reduced pressure.

Example 1-1-7

1.28 g of 4-bromo-3-methylacetophenone, 1.46 g of3′,5′-dichloro-2,2,2-trifluoroacetophenone, 4.38 g of distilled water,0.17 g of potassium carbonate and 35 mg of sodium decanoate were fed andthe mixture was stirred for 6 hours at 80° C. 8.22 g of toluene and 0.4ml of concentrated hydrochloric acid were added to the slurry-statereaction solution. A small amount of the organic phase was taken,diluted with acetonitrile, and analyzed by high-performance liquidchromatography. A percentage of the area of1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-onewas 96.1% (detected by UV detector at a wavelength of 220 nm, andcalculated with omitting the peak of toluene).

Example 1-1-8

1.07 g of 4-bromo-3-methylacetophenone, 1.2 g of3′,5′-dichloro-2,2,2-trifluoroacetophenone, 3.66 g of distilled water,0.14 g of potassium carbonate and 33 mg of sodium laurate were fed andthe mixture was stirred for 14 hours at 70° C. The slurry-state reactionsolution was filtered under reduced pressure, and the solid was washedwith distilled water. 2.10 g of1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-oneas a white solid was obtained by drying under reduced pressure.

Example 1-1-9

0.44 g of 4-bromo-3-methylacetophenone, 0.50 g of3′,5′-dichloro-2,2,2-trifluoroacetophenone, 5.0 g of distilled water,0.14 g of potassium carbonate and 27 mg of sodium dodecane sulfonatewere fed and the mixture was stirred for 6 hours at 80° C. A smallamount of the slurry-state reaction solution was taken, diluted withacetonitrile, and analyzed by high-performance liquid chromatography. Apercentage of the area of1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-onewas 94.5% (detected by UV detector at a wavelength of 220 nm).

Example 1-1-10

0.64 g of 4-bromo-3-methylacetophenone, 0.73 g of3′,5′-dichloro-2,2,2-trifluoroacetophenone, 2.19 g of distilled water,83 mg of potassium carbonate and 11 mg of sodium dodecylbenzenesulfonatewere fed and the mixture was stirred for 5 hours at 80° C. 4.11 g oftoluene and 0.3 ml of concentrated hydrochloric acid were added to theslurry-state reaction solution. A small amount of the organic phase wastaken, diluted with acetonitrile, and analyzed by high-performanceliquid chromatography. A percentage of the area of1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-onewas 95.7% (detected by UV detector at a wavelength of 220 nm, andcalculated with omitting the peak of toluene).

Example 1-1-11

4.26 g of 4-bromo-3-methylacetophenone, 4.86 g of3′,5′-dichloro-2,2,2-trifluoroacetophenone, 20.0 g of distilled water,1.38 g of potassium carbonate and 0.29 g of sodium dodecyl sulfonatewere fed and the mixture was stirred for 5 hours at 80° C. 20.0 g oftoluene and 0.4 ml of concentrated hydrochloric acid were added to theslurry-state reaction solution. The solution was further stirred for 2hours at 80° C., and separated. A small amount of the organic phase wastaken, diluted with acetonitrile, and analyzed by high-performanceliquid chromatography. A percentage of the area of1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-onewas 94.2% (detected by UV detector at a wavelength of 220 nm, andcalculated with omitting the peak of toluene).

Example 1-1-12

1.07 g of 4-bromo-3-methylacetophenone, 1.22 g of3′,5′-dichloro-2,2,2-trifluoroacetophenone, 7.32 g of distilled water,0.35 g of potassium carbonate and 0.72 g of methanol were fed and themixture was stirred for 8 hours at 70° C. 9.16 g of toluene and 0.5 mlof concentrated hydrochloric acid were added to the slurry-statereaction solution. A small amount of the organic phase was taken,diluted with acetonitrile, and analyzed by high-performance liquidchromatography. A percentage of the area of1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-onewas 91.7% (detected by UV detector at a wavelength of 220 nm, andcalculated with omitting the peak of toluene).

Example 1-1-13

0.64 g of 4-bromo-3-methylacetophenone, 0.73 g of3′,5′-dichloro-2,2,2-trifluoroacetophenone, 4.38 g of distilled water,0.21 g of potassium carbonate and 0.44 g of N,N′-dimethylformamide werefed and the mixture was stirred for 7 hours at 70° C. 4.11 g of tolueneand 0.6 ml of concentrated hydrochloric acid were added to theslurry-state reaction solution. A small amount of the organic phase wastaken, diluted with acetonitrile, and analyzed by high-performanceliquid chromatography. A percentage of the area of1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-onewas 95.0% (detected by UV detector at a wavelength of 220 nm, andcalculated with omitting the peak of toluene andN,N′-dimethylformamide).

Example 1-2 Synthesis of4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methylbenzoicAcid and the Salt Thereof Example 1-2-1

0.53 g of 4-acetyl-2-methylbenzoic acid, 0.73 g of3′,5′-dichloro-2,2,2-trifluoroacetophenone, 3.65 g of distilled water,0.48 g of potassium carbonate and 33 mg of sodium laurate were fed andthe mixture was stirred for 9 hours at 60° C. 0.8 ml of concentratedhydrochloric acid was added to the slurry-state reaction solution, andthe solid was extracted with 10 ml of ethyl acetate. 1.27 g of a yellowsolid was obtained by concentrating the organic phase under reducedpressure. This solid was washed with mixed liquid of 5 ml of n-heptaneand 0.5 ml of ethyl acetate to obtain 1.17 g of4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methylbenzoicacid as a flesh color solid.

¹H-NMR (CDCl₃, Me₄Si, 400 MHz) δ 8.17 (d, J=8.2 Hz, 1H), 7.79-7.87 (m,2H), 7.48-7.52 (m, 2H), 7.36 (t, J=1.8 Hz, 1H), 5.61 (br s, 1H), 3.89(d, J=17.4 Hz, 1H), 3.72 (d, J=17.4 Hz, 1H), 2.74 (s, 3H).

Melting point 171-172° C.

Example 1-2-2

4.46 g of 4-acetyl-2-methylbenzoic acid, 6.08 g of3′,5′-dichloro-2,2,2-trifluoroacetophenone, 18.2 g of toluene and 3.79 gof triethylamine were fed and the mixture was stirred for 13 hours at60° C. 12.2 g of toluene was added to the slurry-state reactionsolution, and the mixture was cooled to room temperature. The reactionsolution was filtered under reduced pressure, and the solid was washedwith a small amount of toluene. 11.3 g of triethylamine salt of4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methylbenzoicacid as a white solid was obtained by drying under reduced pressure.

¹H-NMR (CDCl₃, Me₄Si, 400 MHz) δ 7.67-7.76 (m, 3H), 7.49 (d, J=1.8 Hz,2H), 7.33 (t, J=1.8 Hz, 1H), 5.98 (br s, 1H), 3.85 (d, J=17.4 Hz, 1H),3.63 (d, J=17.4 Hz, 1H), 3.12 (q, J=7.1 Hz, 6H), 2.58 (s, 3H), 1.34 (t,J=7.1 Hz, 9H).

Melting point 114-115° C.

Example 1-2-3

0.54 g of 4-acetyl-2-methylbenzoic acid, 0.74 g of3′,5′-dichloro-2,2,2-trifluoroacetophenone, 1.48 g of toluene and 0.34 gof diethylamine were fed and the mixture was stirred for 13 hours at 60°C. 1.48 g of toluene was added to the slurry-state reaction solution,and the mixture was cooled to room temperature. The reaction solutionwas filtered under reduced pressure, and the solid was washed with asmall amount of toluene. 1.42 g of diethylamine salt of4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methylbenzoicacid as a white solid was obtained by drying under reduced pressure.

Melting point 112 to 113° C.

Example 1-2-4

0.54 g of 4-acetyl-2-methylbenzoic acid, 0.74 g of3′,5′-dichloro-2,2,2-trifluoroacetophenone, 1.48 g of toluene and 0.46 gof di-n-propylamine were fed and the mixture was stirred for 6 hours at60° C. 1.48 g of toluene was added to the slurry-state reactionsolution, and the mixture was cooled to room temperature. The reactionsolution was filtered under reduced pressure, and the solid was washedwith a small amount of toluene. 1.48 g of di-n-propylamine salt of4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methylbenzoicacid as a white solid was obtained by drying under reduced pressure.

Melting point 133 to 135° C.

Example 1-2-5

0.54 g of 4-acetyl-2-methylbenzoic acid, 0.74 g of3′,5′-dichloro-2,2,2-trifluoroacetophenone, 1.48 g of toluene and 0.46 gof di-i-propylamine were fed and the mixture was stirred for 6 hours at60° C. 1.48 g of toluene was added to the slurry-state reactionsolution, and the mixture was cooled to room temperature. The reactionsolution was filtered under reduced pressure, and the solid was washedwith a small amount of toluene. 1.39 g of di-i-propylamine salt of4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methylbenzoicacid as a white solid was obtained by drying under reduced pressure.

Melting point 135 to 137° C.

Example 1-2-6

0.54 g of 4-acetyl-2-methylbenzoic acid, 0.74 g of3′,5′-dichloro-2,2,2-trifluoroacetophenone, 1.48 g of toluene and 0.46 gof pyrrolidine were fed and the mixture was stirred for 6 hours at 60°C. 1.48 g of toluene was added to the slurry-state reaction solution,and the mixture was cooled to room temperature. The reaction solutionwas filtered under reduced pressure, and the solid was washed with asmall amount of toluene. 1.32 g of pyrrolidine salt of4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methylbenzoicacid as a white solid was obtained by drying under reduced pressure.

Melting point 156 to 158° C.

Example 1-2-7

3.0 g of 4-acetyl-2-methylbenzoic acid, 4.5 g of3′,5′-dichloro-2,2,2-trifluoroacetophenone, 15.0 g of ethyl acetate and1.85 g of diethylamine were fed and the mixture was stirred for 4 hoursat 50° C. 9.0 g of toluene was added to the slurry-state reactionsolution, and the mixture was cooled to room temperature. Then themixture was further cooled to 0° C., and stirred for 30 minutes at 0° C.The reaction solution was filtered under reduced pressure, and the solidwas washed with a small amount of toluene. 7.63 g of diethylamine saltof4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methylbenzoicacid as a white solid was obtained by drying under reduced pressure.

Example 1-3 Synthesis of4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methylbenzoicAcid Amide Example 1-3-1

0.35 g of 4-acetyl-2-methylbenzoic acid amide, 0.49 g of3′,5′-dichloro-2,2,2-trifluoroacetophenone, 1.72 g of toluene and 0.19 gof tri-n-butylamine were fed and the mixture was stirred for 25 hours at60° C. The mixture was left to cool to room temperature and theslurry-state reaction solution was filtered under reduced pressure, andthe solid was washed with a small amount of toluene. 0.65 g of4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methylbenzoicacid amide as a light yellow solid was obtained by drying under reducedpressure.

¹H-NMR (CDCl₃, Me₄Si, 400 MHz) δ 7.74-7.81 (m, 2H), 7.56 (d, J=8.6 Hz,1H), 7.47-7.51 (m, 2H), 7.36 (t, J=1.8 Hz, 1H), 5.93 (br s, 1H), 5.79(br s, 1H), 5.68 (br s, 1H), 3.84 (d, J=17.4 Hz, 1H), 3.68 (d, J=17.6Hz, 1H), 2.57 (s, 3H).

Melting point 152-154° C.

Example 1-3-2

0.35 g of 4-acetyl-2-methylbenzoic acid amide, 0.49 g of3′,5′-dichloro-2,2,2-trifluoroacetophenone, 2.96 g of distilled water,83 mg of potassium carbonate and 13 mg of sodium laurate were fed andthe mixture was stirred for 5.5 hours at 70° C. The mixture was left tocool to room temperature and the slurry-state reaction solution wasfiltered under reduced pressure, and the solid was washed with a smallamount of distilled water. 0.71 g of4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methylbenzoicacid amide as a flesh color solid was obtained by drying under reducedpressure.

Example 1-4 Synthesis of4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methyl-N-(pyridin-1-ylmethyl)benzoic Acid Amide

1.52 g of 4-acetyl-2-methyl-N-(pyridin-1-ylmethyl) benzoic acid amide,1.51 g of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 1.51 g of tolueneand 0.52 g of tri-n-butylamine were fed and the mixture was stirred for10 hours at 60° C. The mixture was left to cool to room temperature and1 ml of toluene was added to the slurry-state reaction solution. Theslurry was filtered under reduced pressure, and the solid was washedwith a small amount of toluene. 2.16 g of4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methyl-N-(pyridin-2-ylmethyl)benzoic acid amide as a flesh color solid was obtained by drying underreduced pressure.

Example 1-5 Synthesis of ethyl4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methylbenzoate

0.63 g of ethyl 4-acetyl-2-methylbenzoate, 0.73 g of3′,5′-dichloro-2,2,2-trifluoroacetophenone, 0.73 g of n-heptane and 0.30g of triethylamine were fed and the mixture was stirred for 4 hours at60° C. The mixture was left to cool, and further stirred for one nightat room temperature. 0.53 g of n-heptane was added to the slurry-statereaction solution, and the mixture was filtered under reduced pressure.The solid was washed with a small amount of n-heptane, and dried underreduced pressure. 0.97 g of ethyl4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methylbenzoateas a light yellow solid was obtained by drying under reduced pressure.

¹H-NMR (CDCl₃, Me₄Si, 400 MHz) δ 7.98 (d, J=8.6 Hz, 1H), 7.75-7.80 (m,2H), 7.47-7.51 (m, 2H), 7.35 (t, J=1.8 Hz, 1H), 5.64 (br s, 1H), 4.40(q, J=7.1 Hz, 2H), 3.86 (d, J=17.6 Hz, 1H), 3.69 (d, J=17.6 Hz, 1H),2.64 (s, 3H), 1.42 (t, J=7.1 Hz, 3H).

Melting point 72-74° C.

Example 1-6 Synthesis of3-(3,5-bis(trifluoromethyl)phenyl)-1-(3-chloro-4-methylphenyl-4,4,4-trifluoro-3-hydroxybutan-1-one

3.01 g of 3′-chloro-4′-methylacetophenone and 0.99 g of tributylaminewas added to a heptane (6 ml) solution of 6.62 g of3′,5′-bis(trifluoromethyl)-2,2,2-trifluoroacetophenone, and the mixturewas stirred for 2 hours at 60° C. A small amount of crystal of thetarget product was added to the reaction mixture. After confirmingdeposition of the crystal after 1 hour, the reaction mixture was cooledto room temperature. The deposited crystal was collected by filtrationand washed with 2 ml of hexane to obtain 7.55 g of the target product(white crystal).

Melting point 81.0 to 84.0° C. ¹H-NMR (CDCl₃, Me₄Si, 400 MHz) δ 8.06 (s,2H), 7.89 (s, 2H), 7.72 (dd, J=7.8, 1.5 Hz, 1H), 7.38 (d, J=7.8 Hz, 1H),5.90 (s, 1H), 3.85 (d, J=17.4 Hz, 1H), 3.74 (d, J=17.4 Hz, 1H), 2.47 (s,3H).

Example 1-7 Synthesis of1-(4-(1H-1,2,4-triazol-1-yl)phenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one

2.00 g (10.7 mmol) of 1-(4-(1H-1,2,4-triazol-1-yl)phenyl)ethanone, 2.60g (10.7 mmol) of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 5.20 g oftoluene and 0.59 g (3.2 mmol) of tributylamine were fed and the mixturewas stirred for 9 hours at 80° C. After leaving the reaction mixture forone night at room temperature, the deposited solid was filtered underreduced pressure to obtain 3.79 g of1-(4-(1H-1,2,4-triazol-1-yl)phenyl)-3-(3,5-dichlorophenyl-4,4,4-trifluoro-3-hydroxybutan-1-oneas a white solid (yield 82.4%).

Melting point 165 to 166° C.

Example 1-8 Synthesis of1-(4-(1H-imidazol-1-yl)phenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one

0.50 g (2.69 mmol) of 1-(4-(1H-imidazol-1-yl)phenyl)ethanone, 0.65 g(2.69 mmol) of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 1.31 g oftoluene and 0.15 g (0.81 mmol) of tributylamine were fed and the mixturewas stirred for 8 hours at 60° C. After leaving the reaction mixture forone night at room temperature, the solid was filtered under reducedpressure to obtain 0.94 g of1-(4-(1H-imidazol-1-yl)phenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-oneas a white solid (yield 85.7%).

Melting point 161 to 162° C.

Example 1-9 Synthesis of3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxy-1-(4-(methylthio)phenyl)butan-1-one

0.50 g (3.01 mmol) of 1-(4-(methylthio)phenyl)ethanone, 0.73 g of (3.01mmol) of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 1.46 g of tolueneand 0.17 g (0.90 mmol) of tributylamine were fed and the mixture wasstirred for 15 hours at 60° C. After leaving the reaction mixture forone night at room temperature, separation operation was performed byadding 30 ml of ethyl acetate and 10 ml of water, and the ethyl acetatephase was washed with diluted aqueous solution of hydrochloric acid.After removing the solvent by distilling under reduced pressure, theresidue was purified by silica gel column chromatography to obtain 0.56g of3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxy-1-(4-(methylthio)phenyl)butan-1-one(yield 45.2%).

¹H-NMR (CDCl₃, Me₄Si, 300 MHz) δ 7.84 (d, J=8.7 Hz, 2H), 7.50 (bs, 2H),7.34 (d, J=1.8 Hz, 1H), 7.29 (d, J=8.7 Hz, 2H), 5.95 (s, 1H), 3.80 (d,J=17.4 Hz, 1H), 3.61 (d, J=17.4 Hz, 1H), 2.54 (s, 3H).

Example 1-10 Synthesis of1-(6-bromopyridin-3-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one

1.00 g (4.99 mmol) of 1-(6-bromopyridin-3-yl)-ethanone, 1.21 g (4.99mmol) of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 2.42 g of tolueneand 0.28 g (1.50 mmol) of tributylamine were fed and the mixture wasstirred for 13 hours at 60° C. After cooling the reaction solution toroom temperature, the solid was filtered under reduced pressure toobtain 0.85 g of1-(6-bromopyridin-3-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-oneas a white solid (yield 38.4%) Melting point 102-104° C.

Example 1-11 Synthesis of1-(6-(1H-1,2,4-triazol-1-yl)pyridin-3-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one

1.10 g (5.84 mmol) of 1-(6-(1H-1,2,4-triazol-1-yl)pyridin-3-yl)ethanone, 1.42 g (5.84 mmol) of3′,5′-dichloro-2,2,2-trifluoroacetophenone, 2.84 g of toluene and 0.32 g(1.75 mmol) of tributylamine were fed and the mixture was stirred for 7hours at 60° C. After leaving the reaction mixture for one night at roomtemperature, the solid was filtered under reduced pressure to obtain1.84 g of1-(6-(1H-1,2,4-triazol-1-yl)pyridin-3-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-oneas a white solid (yield 73.1%).

Melting point 135 to 136° C.

Example 1-12 Synthesis of5-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-(1H-1,2,4-triazol-1-yl)benzonitrile

1.00 g (4.71 mmol) of 5-acetyl-2-(1H-1,2,4-triazol-1-yl) benzonitrile,1.15 g (4.71 mmol) of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 2.30 gof toluene and 0.26 g (1.41 mmol) of tributylamine were fed and themixture was stirred for 24 hours at 60° C. The mixture was cooled toroom temperature, and a separation operation was performed by adding 20ml of toluene and an aqueous solution prepared with 0.15 g (1.41 mmol)of 35% hydrochloric acid and 10 ml of water. The toluene phase waswashed with 10 ml of water. After removing the solvent by distillingunder reduced pressure, the residue was purified by silica gel columnchromatography to obtain 1.20 g of5-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-(1H-1,2,4-triazol-1-yl)benzonitrile (yield 56.0%).

¹H-NMR (CDCl₃, Me₄Si, 300 MHz) δ 9.00 (s, 1H), 8.39 (d, J=2.1 Hz, H),8.29 (dd, J=9.0 Hz, 2.1 Hz, 1H), 8.24 (s, 1H), 8.06 (d, J=9.0 Hz, 1H),7.48 (d, J=1.5 Hz, 2H), 7.38 (d, J=1.5 Hz, 1H), 5.28 (s, 1H), 3.80 (dd,J=27.3 Hz, 17.4 Hz, 2H).

Example 1-13 Synthesis of5-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-fluorobenzonitrile

1.01 g (6.19 mmol) of 2-acetyl-2-fluorobenzonitrile, 1.50 g (6.19 mmol)of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 3.00 g of toluene and0.34 g (1.86 mmol) of tributylamine were fed and the mixture was stirredfor 16 hours at 60° C. After cooling the reaction solution to roomtemperature, the solid was filtered under reduced pressure to obtain2.06 g of5-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-fluorobenzonitrileas a white solid (yield 82.0%).

Melting point 146 to 147° C.

Example 2-1 Synthesis of1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-oneExample 2-1-1

1.37 g of1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one,2.74 g of toluene and 0.89 g of thionyl chloride were fed, and themixture was heated to 80° C. 0.48 g of pyridine was slowly added indropwise, and the mixture was stirred for 90 minutes at 80° C. Themixture was cooled to room temperature, and separated by adding icedwater. The organic phase was washed with a diluted aqueous solution ofsodium hydroxide, and the solvent was distilled off under reducedpressure. 1.31 g of1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-onewas obtained as a yellow solid.

Example 2-1-2

6.84 g of1-(4-bromo-3-methylphenyl-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one,13.7 g of toluene and 4.46 g of thionyl chloride were fed, and themixture was heated to 70° C. 3.64 g of 2-methyl-5-ethylpyridine wasslowly added in dropwise, and the mixture was stirred for 70 minutes at70° C. The mixture was cooled to room temperature, and separated byadding 6.84 g of water. The organic phase was washed with a dilutedaqueous solution of sodium hydroxide, and the solvent was distilled offunder reduced pressure. 6.60 g of1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-onewas obtained as a yellow solid.

Example 2-1-3

0.91 g of1-(4-bromo-3-methylphenyl-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one,1.82 g of toluene and 0.36 g of thionyl chloride were fed, and themixture was heated to 30° C. 0.56 g of n-tributylamine was slowly addedin dropwise. The mixture was heated to 70° C., and stirred for 7 hours.The mixture was cooled to room temperature, and separated by adding icedwater. The organic phase was washed with water, and the solvent wasdistilled off under reduced pressure. 0.86 g of1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-onewas obtained as a yellow solid.

Example 2-1-4

2.28 g of1-(4-bromo-3-methylphenyl-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one,4 g of toluene and 1.02 g of acetic anhydride were fed, and the mixturewas heated to 70° C. A toluene (0.56 g) solution of 61 mg of4-dimethylaminopyridine, and then 0.59 g of pyridine were slowly addedin dropwise, and the mixture was stirred for 19 hours to heat to 80° C.The mixture was cooled to room temperature and separated by addingwater, and the solvent was distilled off under reduced pressure. 2.20 gof1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-onewas obtained as a yellow solid.

Example 2-1-5

0.91 g of1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one,1.82 g of toluene, 0.41 g of acetic anhydride, 24 mg of4-dimethylaminopyridine and 0.14 g of triethylamine were fed, andstirred for 20 hours at room temperature. 1 ml of water and 0.3 ml ofconcentrated hydrochloric acid were added and separated. The organicphase was washed with saturated aqueous solution of sodium bicarbonate,and the solvent was distilled off under reduced pressure. 0.89 g of1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-onewas obtained as a yellow solid.

Example 2-2 Synthesis of4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoicAcid Example 2-2-1

1.04 g of triethylamine salt of4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl-2-methylbenzoicacid, 1.7 g of toluene and 24 mg of 4-dimethylaminopyridine were fed,and the mixture was heated to 60° C. Then, 0.41 g of acetic anhydridewas added, and the mixture was stirred for 9 hours at 60° C. Thereaction solution was left to cool to room temperature and 3.4 g oftoluene, 2.5 g of water and 0.3 ml of concentrated hydrochloric acidwere added and separated. The organic phase was washed with water, andthe solvent was distilled off under reduced pressure. 0.80 g of4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoicacid was obtained as a yellow solid.

Here, the target compound obtained in this Synthesis Example is amixture of geometric isomers whose ratio determined by ¹H-NMR was about8.6 to 1. ¹H-NMR of mainly produced isomer is shown below.

¹H-NMR (CDCl₃, Me₄Si, 400 MHz) δ 8.11 (d, J=8.6 Hz, 1H), 7.67-7.73 (m,2H), 7.37-7.39 (m, 1H), 7.33 (t, J=1.8 Hz, 1H), 7.16 (br d, J=1.8 Hz,2H), 2.68 (s, 3H). Melting point 128 to 131° C.

Example 2-2-2

3.0 g of4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl-2-methylbenzoicacid, 7.5 g of toluene and 87 mg of 4-dimethylaminopyridine were fed,and the mixture was heated to 80° C. Then, 1.16 g of acetic anhydridewas added in dropwise, and 0.86 g of triethylamine was further added indropwise. After adding in dropwise, the mixture was stirred for 4 hoursat 80° C. 7.5 g of toluene was added to the reaction solution, and thesolution was cooled to room temperature. A water (8.1 g) solution of0.77 g of sodium hydroxide was added in dropwise to the reactionsolution, and the mixture was separated. The organic phase was analyzedby high-performance liquid chromatography (wavelength 254 nm). Twogeometric isomers derived from4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoicacid were produced and each value of area was 82.8% and 16.9%.

Example 2-3 Synthesis of4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoicAcid Amide

0.48 g of4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methylbenzoicacid amide, 1.5 g of toluene, 0.23 g of acetic anhydride, 27 mg of4-dimethylaminopyridine and 0.23 g of triethylamine were fed and themixture was stirred for 2.5 hours at 30° C. 2 ml of iced water and 2drops of concentrated hydrochloric acid were added to the reactionsolution, and the deposited solid was collected by filtration. The solidwas washed with a small amount of toluene and distilled water, and driedunder reduced pressure. 0.32 g of4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoicacid amide was obtained as a flesh color solid.

Here, the target compound obtained in this Synthesis Example is only asingle geometric isomer.

¹H-NMR (CDCl₃, Me₄Si, 400 MHz) δ 7.63-7.70 (m, 2H), 7.51 (d, J=7.7 Hz,1H), 7.36-7.39 (m, 1H), 7.34 (t, J=1.8 Hz, 1H), 7.15 (br d, J=1.8 Hz,2H), 5.84 (br s, 1H), 5.74 (br s, 1H), 2.52 (s, 3H). Melting point 113to 115° C.

Example 2-4 Synthesis of ethyl4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoate

0.96 g of ethyl4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methylbenzoate,2.0 g of toluene, 0.43 g of acetic anhydride, 26 mg of4-dimethylaminopyridine and 0.43 g of triethylamine were fed and themixture was stirred for 3 hours at 30° C. 2 ml of iced water, 2 drops ofconcentrated hydrochloric acid and 5 ml of toluene were added to thereaction solution, and separated. The organic phase was washed withwater, and the solvent was distilled off under reduced pressure toobtain 0.94 g of ethyl4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoateas a red solid.

Here, the target compound obtained in this Synthesis Example is amixture of geometric isomers whose ratio determined by ¹H-NMR was about15 to 1. ¹H-NMR data of mainly produced geometric isomer are shownbelow.

¹H-NMR (CDCl₃, Me₄Si, 400 MHz) δ 7.93 (d, J=8.6 Hz, 1H), 7.63-7.69 (m,2H), 7.37-7.40 (m, 1H), 7.33 (t, J=1.8 Hz, 1H), 7.13-7.16 (m, 2H), 4.38(q, J=7.1 Hz, 2H), 2.62 (s, 3H), 1.41 (t, J=7.1 Hz, 3H). Melting point36 to 38° C.

Example 2-5 Synthesis of4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methyl-N-(pyridin-2-ylmethyl)benzoic Acid Amide

0.78 g of4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methyl-N-(pyridin-2-ylmethyl)benzoic acid amide, 4.3 g of toluene, 0.58 g of acetic anhydride, 20 mgof 4-dimethylaminopyridine, 0.40 g of tri-n-butylamine were fed and themixture was stirred for 2.5 hours at 30° C. 2 ml of iced water was addedto the reaction solution, and the reaction solution was concentratedunder reduced pressure. The residue was passed through a column filledwith silica gel, and the silica gel was washed with a small amount of1:1 mixed solution of n-hexane:ethyl acetate. The organic phases werecombined and the solvent was distilled off under reduced pressure toobtain 0.64 g of4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methyl-N-(pyridin-2-ylmethyl)benzoic acid amide as a yellow solid.

Here, the target compound obtained in this Synthesis Example is amixture of geometric isomers whose ratio determined by ¹H-NMR was 40 to1.

Example 2-6 Synthesis of3-(3,5-bis(trifluoromethyl)phenyl)-1-(3-chloro-4-methylphenyl)-4,4,4-trifluoro-2-buten-1-oneExample 2-6-13-(3,5-bis(trifluoromethyl)phenyl)-1-(3-chloro-4-methylphenyl)-4,4,4-trifluoro-2-buten-1-one

1.15 g of3-(3,5-bis(trifluoromethyl)phenyl)-1-(3-chloro-4-methylphenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one,2.3 g of toluene, 0.49 g of acetic anhydride, 29 mg of4-dimethylaminopyridine and 0.38 g of pyridine were fed, and stirred for9 hours at 70° C. The mixture was cooled to room temperature, andseparated by adding 5 ml of toluene, iced water and 0.6 ml ofconcentrated hydrochloric acid. The organic phase was washed with water,and the solvent was distilled off under reduced pressure. The obtainedresidue was roughly purified by using a small amount of silica gel toobtain 1.09 g of3-(3,5-bis(trifluoromethyl)phenyl)-1-(3-chloro-4-methylphenyl)-4,4,4-trifluoro-2-buten-1-oneas yellow liquid.

Here, the target compound obtained in this Synthesis Example is amixture of geometric isomers whose ratio determined by ¹H-NMR was about10 to 1. ¹H-NMR of mainly produced isomer is shown below.

¹H-NMR (CDCl₃, Me₄Si, 300 MHz) δ 7.87 (s, 1H), 7.77 (d, J=2.1 Hz, 1H),7.73 (s, 2H), 7.61 (dd, J=8.1, 2.1 Hz, 1H), 7.50 (q, J=1.2 Hz, 1H), 7.32(d, J=8.1 Hz, 1H), 2.44 (s, 3H).

Example 2-6-23-(3,5-bis(trifluoromethyl)phenyl)-1-(3-chloro-4-methylphenyl)-4,4,4-trifluoro-2-buten-1-one

0.96 g of3-(3,5-bis(trifluoromethyl)phenyl)-1-(3-chloro-4-methylphenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one,1.92 g of toluene, 0.48 g of thionyl chloride and 0.32 g of pyridinewere fed, and stirred for 6 hours at 70° C. The mixture was cooled toroom temperature, and separated by adding 10 ml of toluene and icedwater. The organic phase was washed with water, and the solvent wasdistilled off under reduced pressure. The obtained residue was roughlypurified by using a small amount of silica gel to obtain 0.92 g of3-(3,5-bis(trifluoromethyl)phenyl)-1-(3-chloro-4-methylphenyl)-4,4,4-trifluoro-2-buten-1-oneas yellow liquid.

Example 2-7 Synthesis of1-(4-(1H-1,2,4-triazol-1-yl)phenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one

After adding 6.00 g of toluene to 2.00 g (4.65 mmol) of1-(4-(1H-1,2,4-triazol-1-yl)phenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one,1.11 g (9.30 mmol) of thionyl chloride and 0.74 g (9.30 mmol) ofpyridine were added at 80° C., and stirred for 3 hours. The reactionsolution was cooled to room temperature, and separated by adding 50 mlof chloroform and 20 ml of water. After washing the organic phase withan aqueous solution of 0.37 g of sodium hydroxide dissolved into 2.0 gof water, then the phase was washed with water. The solvent wasdistilled off under reduced pressure to obtain 1.58 g of1-(4-(1H-1,2,4-triazol-1-yl)phenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one(Yield 82.4%). Here, the target compound obtained in this SynthesisExample is a mixture of geometric isomers whose ratio determined by¹H-NMR was 4 to 1. ¹H-NMR data of mainly produced geometric isomer areshown below.

¹H-NMR (CDCl₃, Me₄Si, 300 MHz) δ 8.67 (s, 1H), 8.15 (m, 1H), 7.96 (dd,J=6.9 Hz, 2.1 Hz, 2H), 7.82 (dd, J=6.9 Hz, 2.1 Hz, 2H), 7.40 (d, J=1.5Hz, 1H), 7.30 (d, J=1.5 Hz, 1H), 7.17 (d, J=1.5 Hz, 2H)

Example 2-8 Synthesis of1-(4-(1H-imidazol-1-yl)phenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one

After adding 2.69 g of toluene to 0.90 g (2.09 mmol) of1-(4-(1H-imidazol-1-yl)phenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one,0.50 g (4.19 mmol) of thionyl chloride and 0.33 g (4.19 mmol) ofpyridine were added at 80° C., and stirred for 1 hour. The reactionsolution was cooled to room temperature, and separated by adding 35 mlof chloroform and 20 ml of water. After washing the organic phase withan aqueous solution of 0.37 g of sodium hydroxide dissolved into 2.0 gof water, the organic phase was washed with an aqueous solution preparedby 0.44 g (4.19 mmol) of 35% hydrochloric acid and 20 ml of water, andthen washed with water. The solvent was distilled off under reducedpressure to obtain 0.70 g of1-(4-(1H-imidazol-1-yl)phenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one(yield 81.7%).

Here, the target compound obtained in this Synthesis Example is amixture of geometric isomers whose ratio determined by ¹H-NMR was 6to 1. ¹H-NMR data of mainly produced geometric isomer are shown below.

¹H-NMR (CDCl₃, Me₄Si, 300 MHz) δ 7.95 (m, 4H), 7.49 (m, 2H), 7.39 (d,J=1.5 Hz, 1H), 7.34 (m, 2H), 7.17 (d, J=1.8 Hz, 2H)

Example 2-9 Synthesis of3-(3,5-dichlorophenyl)-4,4,4-trifluoro-1-(4-(methylthio)phenyl)2-buten-1-one

After adding 1.44 g of toluene to 0.48 g (1.17 mmol) of3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxy-1-(4-(methylthio)phenyl)butan-1-one, 0.28 g (2.34 mmol) of thionyl chloride and 0.19 g (2.34mmol) of pyridine were added at 80° C., and stirred for 3 hours. Thereaction was traced by high-performance liquid chromatography. Since theraw materials did not disappear, 0.14 g (1.17 mmol) of thionyl chlorideand 0.09 g (1.17 mmol) of pyridine were added and stirred for 1 hour.The reaction solution was cooled to room temperature, and separated byadding 20 ml of ethyl acetate and 10 ml of water. After washing theethyl acetate phase with an aqueous solution of 0.14 g of sodiumhydroxide dissolved into 10 ml of water, the phase was washed withwater. The solvent was distilled off under reduced pressure to obtain0.37 g of3-(3,5-dichlorophenyl)-4,4,4-trifluoro-1-(4-(methylthio)phenyl)-2-buten-1-one(yield 81.8%).

Here, the target compound obtained in this Synthesis Example is amixture of geometric isomers whose ratio determined by ¹H-NMR was 5to 1. ¹H-NMR data of mainly produced geometric isomer are shown below.

¹H-NMR (CDCl₃, Me₄Si, 300 MHz) δ 7.73 (dd, J=6.9 Hz, 1.8 Hz, 2H), 7.37(m, 1H), 7.32 (m, 1H), 7.24 (dd, J=6.9 Hz, 1.8 Hz, 2H), 7.16 (d, J=1.8Hz, 2H), 2.52 (s, 3H)

Example 2-10 Synthesis of1-(6-bromopyridin-3-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one

After adding 2.42 g of toluene to 0.81 g (1.82 mmol) of1-(6-bromopyridin-3-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one,0.44 g (3.64 mmol) of thionyl chloride and 0.29 g (3.64 mmol) ofpyridine were added at 80° C., and stirred for 3 hours. The reactionsolution was cooled to room temperature, and separated by adding 15 mlof ethyl acetate and 10 ml of water. After washing the ethyl acetatephase with an aqueous solution of 0.15 g of sodium hydroxide dissolvedinto 10 ml of water, the phase was washed with water. The solvent wasdistilled off under reduced pressure to obtain 0.63 g of1-(6-bromopyridin-3-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one(yield 81.4%).

Here, the target compound obtained in this Synthesis Example is amixture of geometric isomers whose ratio determined by ¹H-NMR was 4to 1. ¹H-NMR data of mainly produced geometric isomer are shown below.

¹H-NMR (CDCl₃, Me₄Si, 300 MHz) δ 8.80 (d, J=2.4 Hz, 1H), 8.04 (dd, J=8.1Hz, 2.4 Hz, 1H), 7.42 (bs, 1H), 7.37 (d, J=2.4 Hz, 1H), 7.32 (d, J=1.8Hz, 1H), 7.15 (d, J=1.8 Hz, 2H)

Example 2-11 Synthesis of1-(6-(1H-1,2,4-triazol-1-yl)pyridin-3-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one

After adding 5.34 g of toluene to 1.78 g (4.12 mmol) of1-(6-(1H-1,2,4-triazol-1-yl)pyridin-3-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one,0.98 g (8.25 mmol) of thionyl chloride and 0.65 g (8.25 mmol) ofpyridine were added at 80° C., and stirred for 3 hours. The reactionsolution was cooled to room temperature, and separated by adding 20 mlof ethyl acetate and 10 ml of water. After washing the ethyl acetatephase with an aqueous solution of 0.33 g of sodium hydroxide dissolvedinto 10 ml of water, the phase was washed with water. The solvent wasdistilled off under reduced pressure to obtain 1.69 g of1-(6-(1H-1,2,4-triazol-1-yl)pyridin-3-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one(yield 99.4%).

Here, the target compound obtained in this Synthesis Example is amixture of geometric isomers whose ratio determined by ¹H-NMR was 13 to2. ¹H-NMR data of mainly produced geometric isomer are shown below.

¹H-NMR (CDCl₃, Me₄Si, 300 MHz) δ 9.22 (s, 1H), 8.88 (d, J=2.4 Hz, 1H),8.29 (dd, J=8.7 Hz, 2.4 Hz, 1H), 8.13 (s, 1H), 8.00 (d, J=8.7 Hz, 1H),7.36 (m, 2H), 7.18 (m, 2H)

Example 2-12 Synthesis of5-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-(1H-1,2,4-triazol-1-yl)benzonitrile

After adding 3.00 g of toluene to 1.00 g (2.19 mmol) of5-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-(1H-1,2,4-triazol-1-yl)benzonitrile, 0.52 g (4.39 mmol) of thionyl chloride and 0.35 g (4.39mmol) of pyridine were added at 80° C., and stirred for 2 hours. Thereaction solution was cooled to room temperature, and separated byadding 20 ml of ethyl acetate and 10 ml of water. After washing theethyl acetate phase with an aqueous solution of 0.18 g of sodiumhydroxide dissolved into 10 ml of water, the phase was washed withwater. The solvent was distilled off under reduced pressure to obtain0.92 g of5-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-(1H-1,2,4-triazol-1-yl)benzonitrile (yield 99.4%).

Here, the target compound obtained in this Synthesis Example is amixture of geometric isomers whose ratio determined by ¹H-NMR was 6to 1. ¹H-NMR data of mainly produced geometric isomer are shown below.

¹H-NMR (CDCl₃, Me₄Si, 300 MHz) δ 8.97 (s, 1H), 8.27 (d, J=2.1 Hz, 1H),8.23 (s, 1H), 8.18 (dd, J=8.4 Hz, 2.1 Hz, 1H), 8.00 (d, J=8.4 Hz, 1H),7.38 (m, 2H), 7.17 (m, 2H)

Example 2-13 Synthesis of5-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-fluorobenzonitrile

After adding 5.85 g of toluene to 1.95 g (4.81 mmol) of5-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-fluorobenzonitrile,1.14 g (9.62 mmol) of thionyl chloride and 0.76 g (9.62 mmol) ofpyridine were added at 80° C., and stirred for 2 hours. The reactionsolution was cooled to room temperature, and separated by adding 20 mlof toluene and 10 ml of water. After washing the toluene phase with anaqueous solution of 0.39 g of sodium hydroxide dissolved into 10 ml ofwater, the phase was washed with water. The solvent was distilled offunder reduced pressure to obtain 1.59 g of5-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-fluorobenzonitrile(yield 85.2%).

Here, the target compound obtained in this Synthesis Example is amixture of geometric isomers whose ratio determined by ¹H-NMR was 5to 1. ¹H-NMR data of mainly produced geometric isomer are shown below.

¹H-NMR (CDCl₃, Me₄Si, 300 MHz) δ 8.10 (m, 2H), 7.42 (m, 1H), 7.33 (m,2H), 7.15 (m, 2H)

Example 3-1 One-Pot Synthesis of1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-oneExample 3-1-1

1.07 g of 4-bromo-3-methylacetophenone, 1.22 g of3′,5′-dichloro-2,2,2-trifluoroacetophenone, 5 ml of toluene and 0.69 gof potassium carbonate were fed and the mixture was refluxed by heatingfor 21 hours. The mixture was cooled to room temperature, and separatedby adding iced water. The solvent was distilled off under reducedpressure, and the residue was purified by silica gel columnchromatography (eluent is a mixed liquid of hexane:ethyl acetate=10:1)to obtain 1.72 g of1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-oneas a red solid.

Example 3-1-2

3.0 g of 4-chloro-3-methylacetophenone, 4.35 g of3′,5′-dichloro-2,2,2-trifluoroacetophenone, 30 ml of 1,2-dichloroethane,2.46 g of potassium carbonate and 0.18 g of triethylamine were fed andthe mixture was refluxed by heating for 16 hours. The reaction solutionwas cooled to room temperature, and separated by adding 200 ml of ethylacetate and iced water. The organic phase was washed with dilutedhydrochloric acid and saturated saline, and dried over anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure. Theresidue was purified by silica gel column chromatography (eluent is amixed liquid of hexane:ethyl acetate=9:1) to obtain 6.2 g of1-(4-chloro-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-oneas brown liquid.

Example 3-1-3

2.13 g of 4-bromo-3-methylacetophenone, 2.43 g of3′,5′-dichloro-2,2,2-trifluoroacetophenone, 2.43 g of toluene and 0.15 gof 1,8-diazabicyclo (5,4,0)-7-undecene were fed and the mixture wasrefluxed by heating for 10 hours. The mixture was cooled to roomtemperature, and separated by adding 20 ml of toluene, iced water and0.3 ml of concentrated hydrochloric acid. The solvent was distilled offunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (eluent is a mixed liquid of hexane:ethylacetate=10:1) to obtain 3.95 g of1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-oneas a brown solid.

Example 3-1-4

0.46 g of 4-bromo-3-methylacetophenone, 0.49 g of3′,5′-dichloro-2,2,2-trifluoroacetophenone, 1.85 g of toluene, 1.85 g ofn-tributylamine and 24 mg of 4-dimethylaminopyridine were fed and themixture was stirred for 10 hours at 30° C. Then, 0.68 g of benzoicanhydride was added, and the mixture was stirred for 36 hours at roomtemperature. 0.11 g of benzoic anhydride was added, and further stirredfor 16 hours. 2.7 g of iced water and 0.3 g of sodium hydroxide wereadded, and separated. The water phase was extracted twice with 3 ml oftoluene. The resultant solution was combined with an organic phase andwas washed with water and the solvent was distilled off under reducedpressure. 0.91 g of1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-onewas obtained as a yellow solid.

Example 3-2 One-Pot Synthesis of1-(4-chloro-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one

3.0 g of 4-chloro-3-methylacetophenone, 4.35 g of3′,5′-dichloro-2,2,2-trifluoroacetophenone, 30 ml of 1,2-dichloroethane,2.46 g of potassium carbonate and 0.18 g of triethylamine were fed andthe mixture was refluxed by heating for 16 hours. The reaction solutionwas cooled to room temperature, and separated by adding 200 ml of ethylacetate and iced water. The organic phase was washed with dilutedhydrochloric acid and saturated saline, and dried over anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure. Theresidue was purified by silica gel column chromatography (eluent is amixed liquid of hexane:ethyl acetate=9:1) to obtain 6.2 g of1-(4-chloro-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-oneas brown liquid.

Synthesis Example of Raw Material 41-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-3-hydroxy-4,4,4-trifluorobutan-1-one

Step 1: Synthesis of methyl 3,5-dichlorobenzoate

10 g of concentrated sulfuric acid was added to a methanol (120 g)solution of 50 g of 3,5-dichlorobenzoic acid, and the mixture wasrefluxed by heating for 5 hours. After cooling the reaction solution toroom temperature, the solvent was distilled off under reduced pressure.The obtained residue was dissolved into 200 g of ethyl acetate, washedwith water (200 g×2), then washed with a saturated aqueous solution ofsodium bicarbonate, and further washed with water. After drying theorganic phase over anhydrous magnesium sulfate, 48.6 g of the targetproduct was obtained as a white solid by removing the solvent bydistilling under reduced pressure.

¹H-NMR (CDCl₃, Me₄Si, 300 MHz) δ 7.90 (s, 2H), 7.54 (s, 1H), 3.94 (s,3H).

Step 2: Synthesis of 3′,5′-dichloro-2,2,2-trifluoroacetophenone

After adding 0.37 g of cesium fluoride to dimethoxyethane (300 g)solution of 25 g of methyl 3,5-dichlorobenzoate and 22.5 g oftrifluoromethyltrimethylsilane under ice cooling, the mixture was warmedto room temperature and stirred for 4 hours. After confirmingdisappearance of the raw materials, 200 g of water was added to thereaction solution, and the mixture was extracted with 200 g of ethylacetate. After dehydration/drying of the organic phase with saturatedsaline and then over anhydrous magnesium sulfate in this order, thesolvent was distilled off under reduced pressure to obtain 35.5 g of1-(3,5-dichlorophenyl)-2,2,2-trifluoro-1-trimethylsilyloxy-1-methoxyethaneas crude yellow liquid. The obtained crude product was dissolved into100 ml of tetrahydrofuran, and 9.75 ml of 1 M tetrahydrofuran solutionof tetrabutylammonium fluoride was added in dropwise at roomtemperature. The mixture was stirred for 2 hours at the sametemperature. After completion of the reaction, the solvent was distilledoff under reduced pressure and the obtained residue was dissolved intoethyl acetate. After washing the organic phase with water and dryingover anhydrous magnesium sulfate, the solvent was distilled off underreduced pressure. 24.2 g of the target product as colorless liquid wasobtained by purifying the obtained residue by distilling under reducedpressure.

Boiling point 87° C. (1.7 kPa) ¹H-NMR (CDCl₃, Me₄Si, 300 MHz) δ7.92-7.93 (m, 2H), 7.70-7.71 (m, 1H).

Step 3: Synthesis of1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-3-hydroxy-4,4,4-trifluorobutan-1-one

Tetrahydrofuran (40 ml) solution of 7.0 g of4-bromo-3-methylacetophenone which can be synthesized in accordance withthe method described in WO 96/19477 pamphlet, was cooled with dryice-acetone to −60° C., and 32.8 ml of 1 M tetrahydrofuran solution oflithium bis(trimethylsilyl) amide was added in dropwise over 30 minutes.After adding in dropwise, the mixture was stirred for 1 hour at the sametemperature. Then, tetrahydrofuran (15 ml) solution of 7.98 g of3′,5′-dichloro-2,2,2-trifluoroacetophenone was added in dropwise. Thereaction solution was slowly warmed to room temperature, and stirred for3 hours at room temperature. After completion of the reaction, 2Nhydrochloric acid was added to the reaction solution, and the solventwas distilled off under reduced pressure. The obtained residue wasdissolved into ethyl acetate and the solution was washed with water.After drying the organic phase over anhydrous magnesium sulfate, thesolvent was distilled off under reduced pressure. 9.19 g of the targetproduct was obtained as a white solid by washing the obtained solid withdiisopropyl ether.

Melting point 141 to 142° C. ¹H-NMR (CDCl₃, Me₄Si, 300 MHz) δ 7.77 (d,J=2.1 Hz, 1H), 7.68 (d, J=8.4 Hz, 1H), 7.48 (dd, J=8.4, 2.1 Hz, 1H),7.49 (brs, 2H), 7.34 (brs, 1H), 5.72 (s, 1H), 3.81 (d, J=17.4 Hz, 1H),3.63 (d, J=17.4 Hz, 1H), 2.48 (s, 3H).

Step 4: Synthesis of1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one

0.391 g of thionyl chloride and 0.104 g of pyridine were added totoluene (3 g) solution of 0.3 g of1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-3-hydroxy-4,4,4-trifluorobutan-1-onesynthesized in Step 3 at room temperature and stirred for 1 hour at 80°C. After completion of the reaction, the reaction solution was cooled toroom temperature, and separated by adding toluene and 2N hydrochloricacid. The organic phase was washed with water, and dried over anhydrousmagnesium sulfate. The solvent was distilled off under reduced pressure.Although the obtained residue includes a mixture of geometric isomers,this residue was purified by silica gel column chromatography whicheluted the residue with ethyl acetate-hexane (1:10) to obtain 0.244 g ofthe target product as a yellow solid.

Synthesis Example of Raw Material 5 Methyl4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl) benzoate

1.98 g of bromine was added to chloroform (50 ml) solution of 2.0 g ofmethyl 4-acetyl-2-benzoate at room temperature, and stirred for 30minutes. Then, the solvent was distilled off under reduced pressure. Theobtained residue was dissolved into 40 ml of tetrahydrofuran, and 2.94 gof triphenylphosphine was added to the solution. After stirring thesolution for 30 minutes at 50° C., the solvent was distilled off underreduced pressure. The obtained residue was dissolved into 50 ml ofchloroform, and 2.72 g of 3′,5′-dichloro-2,2,2-trifluoroacetophenonewhich was synthesized in Step 2 in Synthesis Example 1, and 1.4 g oftriethylamine were added to the solution. The solution was stirred for 4hours at room temperature. Then, the reaction solution was washed withwater (50 ml), and the organic phase was dried over anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure. Theobtained residue was purified by silica gel column chromatography whicheluted the residue with ethyl acetate-hexane (1:9), to obtain 1.0 g ofthe target product as a light yellow solid.

Here, the target product isolated in this Synthesis Example is a mixtureof geometric isomers whose ratio determined by ¹H-NMR was 19 to 1.

Melting point 65.5 to 67.5° C. ¹H-NMR (CDCl₃, Me₄Si, 300 MHz) only maincomponent δ 8.11 (d, J=8.4 Hz, 2H), 7.87 (d, J=8.4 Hz, 2H), 7.30-7.42(m, 2H), 7.15 (d, J=1.8 Hz, 2H), 3.95 (s, 3H).

Synthesis Example of Raw Material 64-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl) benzoic Acid

After adding 51 mg of 1,1′-bis(diphenylphosphino)ferrocene and 10 mg ofpalladium (II) acetate to tertiary-butyl alcohol (10 ml), dioxane (10ml) and water (5 ml) solution of 1.95 g of1-(4-bromophenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-onewhich was synthesized in accordance with Synthesis Example of RawMaterial 5, and 0.56 g of triethylamine in an autoclave, and stirringfor 4 hours at 110° C. under 0.5 MPa of carbon monoxide atmosphere, themixture was left to cool to room temperature. 10 mg of palladium (II)acetate was further added and the mixture was stirred for 4 hours at110° C. under 0.5 MPa of carbon monoxide atmosphere. Then, the mixturewas left to cool to room temperature, and the solid was filtered.Diluted hydrochloric acid was added, and the mixture was extracted withethyl acetate. The organic phase was dried over anhydrous sodiumsulfate, and the solvent was distilled off under reduced pressure. Theobtained residue was purified by silica gel column chromatography whicheluted the residue with ethyl acetate-hexane (1:8), to obtain 1.56 g ofthe target product as a resinous solid.

¹H-NMR (CDCl₃, Me₄Si, 300 MHz) δ 8.18 (d, J=8.5 Hz, 2H), 7.91 (d, J=8.5Hz, 2H), 7.40 (s, 1H), 7.34 (s, 1H), 7.16 (s, 2H).

Synthesis Example of Raw Material 74-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoicAcid

0.25 g of 1,1′-bis(diphenylphosphino)ferrocene and 50 mg of palladium(II) acetate were added to 1,2-dimethoxyethene (20 ml) and water (20 ml)solution of 4.85 g of1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-onewhich was synthesized in accordance with Step 4 in Synthesis Example ofRaw Material 5, and 1.36 g of sodium acetate in an autoclave, andstirred for 5.5 hours at 110° C. under 1.0 MPa of carbon monoxideatmosphere. Then, the mixture was left to cool to room temperature, andthe solid was filtered. Diluted hydrochloric acid was added to thesolid, and the mixture was extracted with ethyl acetate. The organicphase was dehydrated/dried with saturated saline and then over anhydrousmagnesium sulfate in this order, and the solvent was distilled off underreduced pressure. The obtained residue was purified by silica gel columnchromatography which eluted the residue with ethyl acetate-hexane (1:5),and then crystallized from mixed solvent of hexane and small amount ofethyl acetate to obtain 2.6 g of the target product as a white solid.

Here, the target product isolated in this Synthesis Example is a mixtureof geometric isomers whose ratio determined by ¹H-NMR was 10 to 1.

Melting point 123.0 to 126.5° C. ¹H-NMR (CDCl₃, Me₄Si, 300 MHz) onlymain component δ 8.11 (d, J=8.7 Hz, 1H), 7.65-7.70 (m, 2H), 7.30-7.40(m, 2H), 7.16 (d, J=1.8 Hz, 2H), 2.69 (s, 3H).

Example 4-1 Synthesis of3-(4-bromo-3-methylphenyl)-5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazoleExample 4-1-1

0.43 g (1.0 mmol) of1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-onewas dissolved into 2.2 g of toluene, and 1.0 g of dimethylsulfoxide wasadded. The mixture was stirred at 20° C. A solution which was preparedseparately by mixing 0.16 g (4.0 mmol) of sodium hydroxide, 0.5 g ofpurified water and 0.164 g (1.0 mmol) of sulfuric acid salt ofhydroxylamine was added in dropwise to this mixture.

Several drops of the reaction solution were poured into 0.5 mL ofpurified water. The mixture was diluted with 2 mL of acetonitrile, andanalyzed by high-performance liquid chromatography. A percentage of thearea of3-(4-bromo-3-methylphenyl)-5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazoledetermined by high-performance liquid chromatography after 1 hour was95.6% (detected by UV detector at a wavelength of 220 nm, and calculatedwith omitting the peak of toluene).

Example 4-1-2

0.43 g (1.0 mmol) of1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-onewas dissolved into 2.2 g of toluene, and 1.0 g of methanol was added.The mixture was stirred at 20° C. A solution which was preparedseparately by mixing 0.16 g (4.0 mmol) of sodium hydroxide, 0.5 g ofpurified water and 0.164 g (1.0 mmol) of sulfuric acid salt ofhydroxylamine was added in dropwise to this mixture.

Several drops of the reaction solution were poured into 0.5 mL ofpurified water. The mixture was diluted with 2 mL of acetonitrile, andanalyzed by high-performance liquid chromatography. A percentage of thearea of3-(4-bromo-3-methylphenyl)-5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazoledetermined by high-performance liquid chromatography after 6 hours was87.7% (detected by UV detector at a wavelength of 220 nm, and calculatedwith omitting the peak of toluene).

Example 4-1-3

0.43 g (1.0 mmol) of1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-onewas dissolved into 2.2 g of toluene, and the mixture was stirred at 15°C. 0.88 g (2.2 mmol of NaOH) of methanol solution of 10% sodiumhydroxide and 0.132 g (2.0 mmol) of 50% aqueous solution ofhydroxylamine which were prepared separately, were added in dropwise tothis mixture.

Several drops of the reaction solution were poured into 0.5 mL ofpurified water. The mixture was diluted with 2 mL of acetonitrile, andanalyzed by high-performance liquid chromatography. A percentage of thearea of3-(4-bromo-3-methylphenyl)-5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazoledetermined by high-performance liquid chromatography after 1 hour was90.8% (detected by UV detector at a wavelength of 220 nm, and calculatedwith omitting the peak of toluene).

Example 4-1-4

0.43 g (1.0 mmol) of1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-onewas dissolved into 2.2 g of toluene, and the mixture was stirred at 15°C. A solution which was diluted separately by adding 0.5 g of methanolto 0.3857 g (2.0 mmol of NaOMe) of 28% methanol solution of sodiummethoxide and 0.132 g (2.0 mmol) of 50% aqueous solution ofhydroxylamine were added in dropwise to this mixture.

Several drops of the reaction solution were poured into 0.5 mL ofpurified water. The mixture was diluted with 2 mL of acetonitrile, andanalyzed by high-performance liquid chromatography. A percentage of thearea of3-(4-bromo-3-methylphenyl)-5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazoledetermined by high-performance liquid chromatography after 1 hour was92.3% (detected by UV detector at a wavelength of 220 nm, and calculatedwith omitting the peak of toluene).

Example 4-1-5

0.43 g (1.0 mmol) of1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-onewas dissolved into 2.2 g of toluene, and 0.0966 g (0.3 mmol) oftetrabutylammonium bromide was added. The mixture was stirred at 0° C. Asolution which was prepared separately by mixing 0.088 g (2.2 mmol) ofsodium hydroxide, 0.5 g of purified water and 0.132 g (2.0 mmol) of 50%aqueous solution of hydroxylamine was added in dropwise to this mixture.

Several drops of the reaction solution were poured into 0.5 mL ofpurified water. The mixture was diluted with 2 mL of acetonitrile, andanalyzed by high-performance liquid chromatography. A percentage of thearea of3-(4-bromo-3-methylphenyl)-5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazoledetermined by high-performance liquid chromatography after 3 hours was98.6% (detected by UV detector at a wavelength of 220 nm, and calculatedwith omitting the peak of toluene). In addition, whole reaction solutionafter 4 hours was analyzed by high performance liquid chromatographyusing an internal standard method. The yield of3-(4-bromo-3-methylphenyl)-5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazolewas 99.3%. (Internal standard method: Solutions varying compositions ofthe previously isolated target product and a standard substance beingstandard for peak area are prepared. The analytical curve is preparedfrom peak area ratios and weight ratios of the target product and thestandard substance by measuring detection intensity of liquidchromatography analysis. Then, a constant amount of the standardsubstance is precisely added to a constant amount or a whole amount ofthe reaction solution after completion of the reaction, and liquidchromatography analysis is performed. This method is a method ofcalculating a concentration of the target product form the obtained arearatio of peak of the target product and peak of the standard substanceby using the analytical curve. Here, p-Terphenyl was used as thestandard substance.)

Example 4-1-6

2.190 g (5.0 mmol) of1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-onewas dissolved into 10.95 g of toluene, and 4.38 g of dimethylsulfoxidewas added. The mixture was stirred at 15° C. A solution which wasprepared separately by mixing 0.80 g (20.0 mmol) of sodium hydroxide,2.5 g of purified water and 0.82 g (5.0 mmol) of sulfuric acid salt ofhydroxylamine was added in dropwise to this mixture.

6 hours later, a diluted aqueous solution of hydrochloric acid preparedby mixing 1.5 mL of 35% hydrochloric acid and 8.76 g of purified waterwas added to the reaction solution, and 11 mL of toluene was added toseparate. 7 g of purified water was added to the organic phase. Themixture was separated and the organic phase was dried over anhydroussodium sulfate. Toluene was distilled off under reduced pressure. 2.264g of a solid was obtained. The solid was identified as3-(4-bromo-3-methylphenyl)-5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazoleby ¹H-NMR, and the yield was 99%.

Example 4-1-7

2.1941 g (5.0 mmol) of1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-onewas dissolved into 10.95 g of toluene, and 0.32 g (1.0 mmol) oftetrabutylammonium bromide was added. The mixture was stirred undercooling with ice. A solution which was prepared separately by mixing0.44 g (11.0 mmol) of sodium hydroxide, 2.2 g of purified water and0.672 g (10.0 mmol) of 50% aqueous solution of hydroxylamine was addedin dropwise to this mixture. 7 hours later, 0.15 g (0.5 mmol) oftetrabutylammonium bromide was further added, and then stirred for 14hours at room temperature.

22 hours later in total, diluted aqueous solution of hydrochloric acidprepared by mixing 2.5 mL of 35% hydrochloric acid and 7.5 g of purifiedwater was added to the reaction solution, and 4 mL toluene was added toseparate. 4 g of purified water was added to the organic phase, and themixture was separated. Two water phases were combined, and extractedagain with 5 mL of toluene. The organic phase was combined with thepreviously obtained organic phase, and dried over anhydrous sodiumsulfate. Toluene was distilled off under reduced pressure. 2.262 g of asolid was obtained. The solid was identified as3-(4-bromo-3-methylphenyl)-5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazoleby ¹H-NMR, and the yield was 99.8%. The melting point was 108 to 110° C.

Example 4-2 Synthesis of3-(4-chloro-3-methylphenyl)-5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole

0.55 g of toluene and 0.027 g (0.085 mmol) of tetrabutylammonium bromidewere added to 0.110 g (0.28 mmol) of1-(4-chloro-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one,and the mixture was stirred at 0° C. A solution which was preparedseparately by mixing 0.025 g (0.61 mmol) of sodium hydroxide, 0.17 g ofpurified water and 0.037 g (0.56 mmol) of 50% aqueous solution ofhydroxylamine was added in dropwise to this mixture.

A small amount of the reaction solution was taken, diluted to 1 mL withacetonitrile, and analyzed by high-performance liquid chromatography. Apercentage of the area of3-(4-chloro-3-methylphenyl)-5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazoledetermined by high-performance liquid chromatography after 7.5 hours was88.4% (detected by UV detector at a wavelength of 225 nm, and calculatedwith omitting the peak of toluene). The reaction temperature was setback to room temperature again, and the reaction was performed for 15hours. The reaction was traced by high-performance liquid chromatographyin the same method as described above, and disappearance of the rawmaterials was confirmed. 0.70 g (1.68 mmol) of 8.8% hydrochloric acidand 5 mL of toluene were added to the reaction solution and separationoperation was performed. The toluene phase was washed with 1 mL ofpurified water, and the water phase was extracted again with 5 mL oftoluene. After combining toluene phases and drying over sodium sulfate,the solvent was distilled off using a rotary evaporator to obtain 0.108g of3-(4-chloro-3-methylphenyl)-5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole(yield 95%). The melting point was 110 to 111° C.

Example 4-3 Synthesis of4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoicAcid Example 4-3-1

0.55 g of toluene and 0.026 g (0.082 mmol) of tetrabutylammonium bromidewere added to 0.110 g (0.27 mmol) of4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoicacid, and the mixture was stirred at 0° C. A solution which was preparedseparately by mixing 0.024 g (0.60 mmol) of sodium hydroxide, 0.17 g ofpurified water and 0.036 g (0.55 mmol) of 50% aqueous solution ofhydroxylamine was added in dropwise to this mixture.

A small amount of the reaction solution was taken, diluted to 1 mL withacetonitrile, and analyzed by high-performance liquid chromatography.Disappearance of the raw materials was confirmed by high-performanceliquid chromatography analysis after 2.5 hours. 0.68 g (1.64 mmol) of8.8% hydrochloric acid and 5 mL of ethyl acetate were added to thereaction solution and separation operation was performed. The ethylacetate phase was washed with 1 mL of purified water, and the waterphase was extracted again with 5 mL of ethyl acetate. After combiningethyl acetate phases and drying over sodium sulfate, the solvent wasdistilled off using a rotary evaporator to obtain 0.111 g of4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoicacid (yield 97%).

Example 4-3-2

3.2 g of dimethylformamide was added to solution in which 1.61 g of4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoicacid was dissolved into 8.51 g of toluene, and the mixture was cooled to0° C. A solution in which 0.64 g of sodium hydroxide was dissolved into1.6 g of water was added to the mixture, and a solution in which 0.46 gof hydroxylamine sulfate dissolved into 1.11 g of water was slowly addedin dropwise with care not to generate heat. After reacting the mixturefor 3 hours with stirring while keeping the reaction temperature at 0°C., the resultant solution was analyzed by high-performance liquidchromatography (wavelength 254 nm). The target product of4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoicacid was produced in 90.49% of relative area.

Example 4-3-3

6.27 g of dimethylsulfoxide was added to solution in which 1.61 g of4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoicacid was dissolved into 10.5 g of toluene, and the mixture was cooled to0° C. A solution in which 0.64 g of sodium hydroxide was dissolved into1.6 g of water was carefully added to the mixtures so that thetemperature of the reaction solution did not exceed 5° C. Moreover, asolution in which 0.46 g of hydroxylamine sulfate was dissolved into2.24 g of water was carefully added to the mixtures so that thetemperature of the reaction solution did not exceed 5° C. The reactionwas performed for 1 hour with stirring while keeping the reactiontemperature at 0° C. The reaction solution was analyzed byhigh-performance liquid chromatography (detected by UV detector at awavelength of 254 nm, and calculated with omitting the peak of toluene).The target product of4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoicacid was produced in 85.0% of relative area.

Example 4-3-4

6.27 g of N-methylpyrrolidone was added to solution in which 1.61 g of4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoicacid was dissolved into 10.5 g of toluene, and the mixture was cooled to−25° C. A solution in which 0.64 g of sodium hydroxide was dissolvedinto 1.6 g of water was carefully added to the mixtures so that thetemperature of the reaction solution did not exceed −20° C. Moreover, asolution in which 0.46 g of hydroxylamine sulfate was dissolved into2.24 g of water was carefully added to the mixtures so that thetemperature of the reaction solution did not exceed −20° C. The reactionwas performed for 3 hours with stirring while keeping the reactiontemperature at −25° C. 10.4 g of toluene and 1.9 ml of 35% hydrochloricacid was added to the reaction solution in dropwise at −25 to −10° C.,and further stirred for 1 hour at room temperature. The reactionsolution was separated and the water phase was extracted with 10.4 g oftoluene. The organic phases were combined and washed with 5 ml of water.The obtained toluene was analyzed by high-performance liquidchromatography using the internal standard method. The yield of4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoicacid was 95.8%.

Example 4-3-5

6.27 g of 1,2-dimethoxyethane was added to solution in which 1.61 g of4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoicacid was dissolved into 10.5 g of toluene, and the mixture was cooled to0° C. A solution in which 0.64 g of sodium hydroxide was dissolved into1.6 g of water was carefully added to the mixture so that thetemperature of the reaction solution did not exceed 5° C. Moreover, asolution in which 0.46 g of hydroxylamine sulfate was dissolved into2.24 g of water was carefully added to the mixture so that thetemperature of the reaction solution did not exceed 5° C. The reactionwas performed for 3 hours with stirring while keeping the reactiontemperature at 0° C. The reaction solution was analyzed byhigh-performance liquid chromatography (detected by UV detector at awavelength of 254 nm, and calculated with omitting the peak of toluene).The target product of4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoicacid was produced in 88.4% of relative area.

Example 4-3-6

3.2 g of diglyme was added to a solution in which 1.61 g of4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoicacid was dissolved into 8.51 g of toluene, and the mixture was cooled to0° C. A solution in which 0.64 g of sodium hydroxide was dissolved into1.6 g of water was added to the mixture, and a solution in which 0.46 gof hydroxylamine sulfate was dissolved into 1.11 g of water was slowlyadded in dropwise with care not to generate heat. After reacting themixture for 1 hour with stirring while keeping the reaction temperatureat 0° C., the resultant solution was analyzed by high-performance liquidchromatography (wavelength 254 nm). The target product of4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoicacid was produced in 88.32% of relative area.

Example 4-3-7

3.2 g of methyl alcohol was added to a solution in which 1.61 g of4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoicacid was dissolved into 8.51 g of toluene, and the mixture was cooled to0° C. A solution in which 0.64 g of sodium hydroxide was dissolved into1.6 g of water was added to the mixture, and a solution in which 0.46 gof hydroxylamine sulfate was dissolved into 1.11 g of water was slowlyadded in dropwise with care not to generate heat. After reacting themixture for 3 hours with stirring while keeping the reaction temperatureat 0° C., the resultant solution was analyzed by high-performance liquidchromatography (wavelength 254 nm). The target product of4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoicacid was produced in 85.49% of relative area.

Example 4-3-8

6.72 g of N-methylpyrrolidone was added to a solution in which 1.73 g of4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoicacid was dissolved into 11.2 g of toluene, and the mixture was cooled to0° C. A solution in which 0.97 g of potassium hydroxide was dissolvedinto 1.7 g of water was carefully added to the mixture so that thetemperature of the reaction solution did not exceed 5° C. Moreover, asolution in which 0.49 g of hydroxylamine sulfate was dissolved into2.40 g of water was carefully added to the mixtures so that thetemperature of the reaction solution did not exceed 5° C. The reactionwas performed for 3 hours with stirring while keeping the reactiontemperature at 0° C. 11.2 g of toluene and 2.1 ml of 35% hydrochloricacid was added to the reaction solution in dropwise at 0 to 5° C., andfurther stirred for 30 minutes at room temperature. The reactionsolution was separate and the water phase was extracted with 12 g oftoluene. The organic phases were combined and washed twice with 5 ml ofwater. The obtained toluene was analyzed by high-performance liquidchromatography using the internal standard method. The yield of4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoicacid was 88.2%.

Example 4-3-9

6.27 g of N-methyl-2-pyrrolidone was added to 11.85 g of toluenesolution which dissolved 1.61 g (4.0 mmol) of4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoicacid, and the mixture was cooled to −7° C. After adding 2.24 g (16 mmol)of an aqueous solution of sodium hydroxide prepared in 10 M in dropwise,and then adding an aqueous solution in which 0.306 g (4.4 mmol) ofhydroxylamine hydrochloride was dissolved into 0.65 g of water indropwise, the mixture was reacted at −7° C. A small amount of thereaction solution was taken, diluted to 1 mL with acetonitrile, andanalyzed by high-performance liquid chromatography. A percentage of thearea of4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoicacid determined by high-performance liquid chromatography after 3 hourswas 98.0% (detected by UV detector at a wavelength of 254 nm, andcalculated with omitting the peak of toluene). 10.4 g of toluene wasadded to the reaction solution after 5 hours, and 1.9 mL of 35%hydrochloric acid was added in dropwise at 0° C., and further stirredfor 1 hour. After stopping stirring, the water phase was removed. Theobtained toluene solution was analyzed by high-performance liquidchromatography using the internal standard method. The yield of4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoicacid was 90.2%.

Example 4-3-10

6.27 g of N-methyl-2-pyrrolidone was added to 11.85 g of toluenesolution which dissolved 1.61 g (4.0 mmol) of4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoicacid, and the mixture was cooled to 0° C. After adding in dropwise asolution prepared by adding 1.6 g of water to 2.44 g (16 mmol) of1,8-diazabicyclo (5,4,0)-7-undecene, and then adding an aqueous solutionin which 0.306 g (4.4 mmol) of hydroxylamine hydrochloride was dissolvedinto 0.65 g of water in dropwise, the mixture was reacted at 0° C. Asmall amount of the reaction solution was taken, diluted to 1 mL withacetonitrile, and analyzed by high-performance liquid chromatography. Apercentage of the area of4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoicacid determined by high-performance liquid chromatography after 3 hourswas 94.9% (detected by UV detector at a wavelength of 254 nm, andcalculated with omitting the peak of toluene). 1.9 mL of 35%hydrochloric acid was added to the reaction solution after 3 hours indropwise at 0° C., and stirred for 1 hour. After stopping stirring, thewater phase was removed. The obtained toluene solution was analyzed byhigh-performance liquid chromatography using the internal standardmethod. The yield of4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoicacid was 92.2%.

Example 4-3-11

6.27 g of ethanol was added to 11.89 g of toluene solution whichdissolved 1.61 g (4.0 mmol) of4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoicacid, and the mixture was cooled to 0° C. After adding in dropwise asolution which was prepared by adding 1.6 g of water to 2.44 g (16 mmol)of 1,8-diazabicyclo (5,4,0)-7-undecene, then adding an aqueous solutionin which 0.306 g (4.4 mmol) of hydroxylamine hydrochloride was dissolvedinto 0.65 g of water in dropwise, the mixture was reacted at 0° C. Asmall amount of the reaction solution was taken, diluted to 1 mL withacetonitrile, and analyzed by high-performance liquid chromatography. Apercentage of the area of4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoicacid determined by high-performance liquid chromatography after 1 hourwas 94.5% (detected by UV detector at a wavelength of 254 nm, andcalculated with omitting the peak of toluene). 1.9 mL of 35%hydrochloric acid was added to the reaction solution after 3 hours indropwise at 0° C., and stirred for 1 hour. After stopping stirring, thewater phase was removed. The obtained toluene solution was analyzed byhigh-performance liquid chromatography using the internal standardmethod. The yield of4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoicacid was 90.4%.

Example 4-3-12

6.27 g of tetrahydrofuran was added to 11.89 g of toluene solution whichdissolved 1.61 g (4.0 mmol) of4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoicacid, and the mixture was cooled to 0° C. After adding in dropwise asolution which was prepared by adding 1.6 g of water to 2.44 g (16 mmol)of 1,8-diazabicyclo (5,4,0)-7-undecene, then adding an aqueous solutionin which 0.306 g (4.4 mmol) of hydroxylamine hydrochloride was dissolvedinto 0.65 g of water in dropwise, the mixture was reacted at 0° C. Asmall amount of the reaction solution was taken, diluted to 1 mL withacetonitrile, and analyzed by high-performance liquid chromatography. Apercentage of the area of4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoicacid determined by high-performance liquid chromatography after3-hour-reaction was 94.0% (detected by UV detector at a wavelength of254 nm, and calculated with omitting the peak of toluene). 1.9 mL of 35%hydrochloric acid was added to the reaction solution after 3 hours indropwise at 0° C., and stirred for 1 hour. After stopping stirring, thewater phase was removed. The obtained toluene solution was analyzed byhigh-performance liquid chromatography using the internal standardmethod. The yield of4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoicacid was 95.2%.

Example 4-3-13

A solution in which 2.02 g of4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoicacid was dissolved into 10.1 g of toluene was cooled to 0° C. 2.28 g of1,8-diazabicyclo (5,4,0)-7-undecene was carefully added to the solutionso that the temperature of the reaction solution did not exceed 5° C.Moreover, a solution in which 0.38 g of hydroxylamine hydrochloride wasdissolved into 0.81 g of water was carefully added to the mixture sothat the temperature of the reaction solution did not exceed 5° C. Thereaction was performed for 2 hours with stirring while keeping thereaction temperature at 0° C. 2.0 ml of 35% hydrochloric acid was addedto the reaction solution in dropwise at 10° C. or lower, and 10 g oftoluene was further added and stirred at room temperature. The reactionsolution was separated and the organic phase was washed twice with 5 mlof water. The obtained toluene was analyzed by high-performance liquidchromatography using the internal standard method. The yield of4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoicacid was 90.4%.

Example 4-3-14

The solution in which 2.02 g of4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoicacid was dissolved into 10.1 g of toluene was cooled to 0° C. 1.52 g of1,8-diazabicyclo (5,4,0)-7-undecene was carefully added to the solutionso that the temperature of the reaction solution did not exceed 5° C.Moreover, the solution in which 0.20 g of sodium hydroxide was dissolvedinto 1.0 g of water was carefully added to the mixture so that thetemperature of the reaction solution did not exceed 5° C. Then, thesolution in which 0.38 g of hydroxylamine hydrochloride was dissolvedinto 0.81 g of water was carefully added to the mixture so that thetemperature of the reaction solution did not exceed 5° C. The reactionwas performed for 2 hours with stirring while keeping the reactiontemperature at 0° C. 2.0 ml of 35% hydrochloric acid was added to thereaction solution in dropwise at 10° C. or lower, and 10 g of toluenewas further added and stirred at room temperature. The reaction solutionwas separated and the organic phase was washed twice with 5 ml of water.The obtained toluene was analyzed by high-performance liquidchromatography using the internal standard method. The yield of4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoicacid was 92.8%.

Example 4-4 Synthesis of methyl4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)benzoate

0.55 g of toluene and 0.026 g (0.082 mmol) of tetrabutylammonium bromidewas added to 0.110 g (0.27 mmol) of methyl4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl) benzoate, and themixture was stirred at 0° C. A solution which was prepared separately bymixing 0.024 g (0.60 mmol) of sodium hydroxide, 0.17 g of purified waterand 0.036 g (0.55 mmol) of 50% aqueous solution of hydroxylamine wasadded in dropwise to this mixture.

A small amount of the reaction solution was taken, diluted to 1 mL withacetonitrile, and analyzed by high-performance liquid chromatography.Disappearance of the raw materials was confirmed by high-performanceliquid chromatography analysis after 5.5 hours. 0.68 g (1.64 mmol) of8.8% hydrochloric acid and 5 mL of toluene were added to the reactionsolution and separation operation was performed. The toluene phase waswashed with 1 mL of purified water, and the water phase was extractedagain with 5 mL of toluene. After combining toluene phases and dryingover sodium sulfate, the solvent was distilled off using a rotaryevaporator to obtain 0.109 g of methyl4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)benzoate (yield 96%).

Example 4-5 Synthesis ofN-(2-pyridylmethyl)-4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoicAcid Amide

0.55 g of toluene and 0.022 g (0.067 mmol) of tetrabutylammonium bromidewere added to 0.110 g (0.22 mmol) ofN-(2-pyridylmethyl)-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoicacid amide, and the mixture was stirred at 0° C. A solution which wasprepared separately by mixing 0.020 g (0.49 mmol) of sodium hydroxide,0.17 g of purified water and 0.029 g (0.45 mmol) of 50% aqueous solutionof hydroxylamine was added in dropwise to this mixture.

A small amount of the reaction solution was taken, diluted to 1 mL withacetonitrile, and analyzed by high-performance liquid chromatography. Apercentage of the area ofN-(2-pyridylmethyl)-4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoicacid amide determined by high-performance liquid chromatography after 23hours was 87.0% (detected by UV detector at a wavelength of 225 nm, andcalculated with omitting the peak of toluene). The reaction temperaturewas set back to room temperature again, and the reaction was performedfor 6 hours. The reaction was traced by high-performance liquidchromatography in the same method as described above, and disappearanceof the raw materials was confirmed. 0.56 g (1.34 mmol) of 8.8%hydrochloric acid and 5 mL of chloroform were added to the reactionsolution and separation operation was performed. The chloroform phasewas washed with 1 mL of purified water, and the water phase wasextracted again with 5 mL of chloroform. After combining chloroformphases and drying over sodium sulfate, the solvent was distilled offusing a rotary evaporator to obtain 0.0836 g ofN-(2-pyridylmethyl)-4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoicacid amide (yield 74%).

Example 4-6 Synthesis of3-(4-bromo-3-methylphenyl)-5-(3,4,5-trichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole

0.29 g of toluene and 0.012 g (0.036 mmol) of tetrabutylammonium bromidewere added to 0.057 g (0.12 mmol) of1-(4-bromo-3-methylphenyl)-3-(3,4,5-trichlorophenyl)-4,4,4-trifluoro-2-buten-1-one,and the mixture was stirred at 0° C. A solution which was preparedseparately by mixing 0.011 g (0.27 mmol) of sodium hydroxide, 0.09 g ofpurified water and 0.016 g (0.24 mmol) of 50% aqueous solution ofhydroxylamine was added in dropwise to this mixture.

A small amount of the reaction solution was taken, diluted to 1 mL withacetonitrile, and analyzed by high-performance liquid chromatography.Disappearance of the raw materials was confirmed by high-performanceliquid chromatography analysis after 23 hours. 0.30 g (0.73 mmol) of8.8% hydrochloric acid and 5 mL of toluene were added to the reactionsolution and separation operation was performed. The toluene phase waswashed with 1 mL of purified water, and the water phase was extractedagain with 5 mL of toluene. After combining toluene phases and dryingover sodium sulfate, the solvent was distilled off using a rotaryevaporator to obtain 0.061 g of3-(4-bromo-3-methylphenyl)-5-(3,4,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole(yield 100%).

¹H-NMR (CDCl₃, Me₄Si, 300 MHz) δ 7.64 (s, 2H), 7.59 (d, 1=8.1 Hz, 1H),7.53 (d, J=2.1 Hz, 1H), 7.32 (dd, J=8.1, 2.1 Hz, 1H), 4.07 (d, J=17.4Hz, 1H), 3.66 (d, J=17.4 Hz, 1H), 2.43 (s, 3H).

Example 4-7 Synthesis of4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)benzoic Acid

1.0 g of toluene and 0.050 g (0.15 mmol) of tetrabutylammonium bromidewere added to 0.200 g (0.51 mmol) of methyl4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl) benzoic acid, andthe mixture was stirred at 0° C. A solution which was preparedseparately by mixing 0.045 g (1.13 mmol) of sodium hydroxide, 0.30 g ofpurified water and 0.068 g (1.03 mmol) of 50% aqueous solution ofhydroxylamine was added in dropwise to this mixture.

A small amount of the reaction solution was taken, diluted to 1 mL withacetonitrile, and analyzed by high-performance liquid chromatography.Disappearance of the raw materials was confirmed by high-performanceliquid chromatography analysis after 6.5 hours. 1.29 g (3.09 mmol) of8.8% hydrochloric acid and 5 mL of ethyl acetate were added to thereaction solution and separation operation was performed. The ethylacetate phase was washed with 1 mL of purified water, and the waterphase was extracted again with 5 mL of ethyl acetate. After combiningethyl acetate phases and drying over sodium sulfate, the solvent wasdistilled off using a rotary evaporator to obtain 0.210 g of4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)benzoic acid (yield 100%).

Example 4-8 Synthesis of3-(4-bromo-3-methylphenyl)-5-(3-trifluoromethylphenyl)-5-trifluoromethyl-4,5-dihydroisoxazole

0.67 g of toluene and 0.030 g (0.092 mmol) of tetrabutylammonium bromidewere added to 0.134 g (0.31 mmol) of1-(4-bromo-3-methylphenyl)-3-(3-trifluoromethylphenyl)-4,4,4-trifluoro-2-buten-1-one,and the mixture was stirred at 0° C. A solution which was preparedseparately by mixing 0.027 g (0.68 mmol) of sodium hydroxide, 0.20 g ofpurified water and 0.041 g (0.61 mmol) of 50% aqueous solution ofhydroxylamine was added in dropwise to this mixture.

A small amount of the reaction solution was taken, diluted to 1 mL withacetonitrile, and analyzed by high-performance liquid chromatography. Apercentage of the area of3-(4-bromo-3-methylphenyl)-5-(3-trifluoromethylphenyl)-5-trifluoromethyl-4,5-dihydroisoxazoledetermined by high-performance liquid chromatography after 22 hours was86.3% (detected by UV detector at a wavelength of 225 nm, and calculatedwith omitting the peak of toluene). The reaction temperature was setback to room temperature again, and the reaction was performed for 5.5hours. The reaction was traced by high-performance liquid chromatographyin the same method as described above, and disappearance of the rawmaterials was confirmed. 0.77 g (1.84 mmol) of 8.8% hydrochloric acidand 5 mL of ethyl acetate were added to the reaction solution andseparation operation was performed. The ethyl acetate phase was washedwith 1 mL of purified water, and the water phase was extracted againwith 5 mL of ethyl acetate. After combining ethyl acetate phases anddrying over sodium sulfate, the solvent was distilled off using a rotaryevaporator to obtain 0.134 g of3-(4-bromo-3-methylphenyl)-5-(3-trifluoromethylphenyl)-5-trifluoromethyl-4,5-dihydroisoxazole(yield 97%). The melting point was 84 to 85° C.

Example 4-9 Synthesis of5-(3,5-bis(trifluoromethyl)phenyl)-3-(4-bromo-3-methylphenyl)-5-trifluoromethyl-4,5-dihydroisoxazole

0.38 g of toluene and 0.015 g (0.045 mmol) of tetrabutylammonium bromidewere added to 0.075 g (0.15 mmol) of3-(3,5-bis(trifluoromethyl)phenyl-1-(4-bromo-3-methylphenyl)-4,4,4-trifluoro-2-buten-1-one,and the mixture was stirred at 0° C. A solution which was preparedseparately by mixing 0.013 g (0.33 mmol) of sodium hydroxide, 0.11 g ofpurified water and 0.020 g (0.30 mmol) of 50% aqueous solution ofhydroxylamine was added in dropwise to this mixture.

A small amount of the reaction solution was taken, diluted to 1 mL withacetonitrile, and analyzed by high-performance liquid chromatography. Apercentage of the area of5-(3,5-bis(trifluoromethyl)phenyl)-3-(4-bromo-3-methylphenyl)-5-trifluoromethyl-4,5-dihydroisoxazoledetermined by high-performance liquid chromatography after 22 hours was94.8% (detected by UV detector at a wavelength of 225 nm, and calculatedwith omitting the peak of toluene). The reaction temperature was setback to room temperature again, and the reaction was performed for 5.5hours. The reaction was traced by high-performance liquid chromatographyin the same method as described above, and disappearance of the rawmaterials was confirmed. 0.38 g (0.90 mmol) of 8.8% hydrochloric acidand 5 mL of ethyl acetate were added to the reaction solution andseparation operation was performed. The ethyl acetate phase was washedwith 1 mL of purified water, and the water phase was extracted againwith 5 mL of ethyl acetate. After combining ethyl acetate phases anddrying over sodium sulfate, the solvent was distilled off using a rotaryevaporator to obtain 0.074 g of5-(3,5-bis(trifluoromethyl)phenyl)-3-(4-bromo-3-methylphenyl)-5-trifluoromethyl-4,5-dihydroisoxazole(yield 95%). The melting point was 108 to 110° C.

Example 4-10 Synthesis of3-(4-bromo-3-methylphenyl)-5-(3,5-dichlorophenyl)-5-chlorodifluoromethyl-4,5-dihydroisoxazole

0.52 g of toluene and 0.022 g (0.068 mmol) of tetrabutylammonium bromidewere added to 0.103 g (0.23 mmol) of1-(4-chloro-3-methylphenyl)-3-(3,5-dichlorophenyl)-4-chloro-4,4-difluoro-2-buten-1-one,and the mixture was stirred at 0° C. A solution which was preparedseparately by mixing 0.020 g (0.50 mmol) of sodium hydroxide, 0.16 g ofpurified water and 0.030 g (0.45 mmol) of 50% aqueous solution ofhydroxylamine was added in dropwise to this mixture.

A small amount of the reaction solution was taken, diluted to 1 mL withacetonitrile, and analyzed by high-performance liquid chromatography. Apercentage of the area of3-(4-bromo-3-methylphenyl)-5-(3,5-dichlorophenyl)-5-chlorodifluoromethyl-4,5-dihydroisoxazoledetermined by high-performance liquid chromatography after 22 hours was57.3% (detected by UV detector at a wavelength of 225 nm, and calculatedwith omitting the peak of toluene). The reaction temperature was setback to room temperature again, and the reaction was performed for 24hours. The reaction was traced by high-performance liquid chromatographyin the same method as described above. As a result, a percentage of thearea of3-(4-bromo-3-methylphenyl)-5-(3,5-dichlorophenyl)-5-chlorodifluoromethyl-4,5-dihydroisoxazolewas 84.7% (detected by UV detector at a wavelength of 225 nm, andcalculated with omitting the peak of toluene). Although the reactionsolution was further stirred for 24 hours at room temperature, thepercentage of the area was not changed. Therefore, the reaction wasterminated, and 0.57 g (1.36 mmol) of 8.8% hydrochloric acid and 5 mL oftoluene were added to the reaction solution and separation operation wasperformed. The toluene phase was washed with 1 mL of purified water, andthe water phase was extracted again with 5 mL of toluene. Aftercombining toluene phases and drying over sodium sulfate, the solvent wasdistilled off using a rotary evaporator. The residue was purified bycolumn chromatography to obtain 0.223 g of3-(4-bromo-3-methylphenyl)-5-(3,5-dichlorophenyl)-5-chlorodifluoromethyl-4,5-dihydroisoxazole(yield 21%).

¹H-NMR (CDCl₃, Me₄Si, 300 MHz) δ 7.58 (d, J=8.1 Hz, 1H), 7.52 (bs, 3H),7.41 (m, 1H), 7.32 (dd, J=8.1, 2.1 Hz, 1H), 4.11 (d, J=17.4 Hz, 1H),3.70 (d, J=17.4 Hz, 1H), 2.44 (s, 3H).

Example 4-11 Synthesis of5-(3,5-bis(trifluoromethyl)phenyl)-3-(3-chloro-4-methylphenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole

0.550 g of toluene and 0.330 g of N-methyl-2-pyrrolidone were added to0.110 g (0.24 mmol) of3-(3,5-bis(trifluoromethyl)phenyl)-1-(3-chloro-4-methylphenyl)-4,4,4-trifluoro-2-buten-1-one,and the mixture was cooled to 0° C. After adding 0.134 g (0.96 mmol) ofan aqueous solution of sodium hydroxide prepared in 10 M in dropwise,and then adding aqueous solution in which 0.018 g (0.26 mmol) ofhydroxylamine hydrochloride was dissolved into 0.039 g of water indropwise, the mixture was reacted at 0° C. A small amount of thereaction solution was taken, diluted to 1 mL with acetonitrile, andanalyzed by high-performance liquid chromatography. A percentage of thearea of5-(3,5-bis(trifluoromethyl)phenyl)-3-(3-chloro-4-methylphenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazoledetermined by high-performance liquid chromatography after 4 hours was96.6% (detected by UV detector at a wavelength of 254 nm, and calculatedwith omitting the peak of toluene). The reaction temperature was setback to room temperature again, and the reaction was performed for 2hours. The reaction was traced by high-performance liquid chromatographyin the same method as described above, and disappearance of the rawmaterials was confirmed. 0.60 g (1.43 mmol) of 8.8% hydrochloric acidand 5 mL of toluene were added to the reaction solution and separationoperation was performed. After washing the toluene phase thrice with 4ml of purified water and drying over sodium sulfate, the solvent wasdistilled off using a rotary evaporator to obtain 0.109 g of5-(3,5-bis(trifluoromethyl)phenyl)-3-(3-chloro-4-methylphenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole(yield 99%).

Example 4-12 Synthesis of3-(4-(1H-1,2,4-triazol-1-yl)phenyl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole

2.50 g of toluene and 1.50 g of N-methyl-2-pyrrolidone was added to 0.50g (1.21 mmol) of3-(4-(1H-1,2,4-triazol-1-yl)phenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one,and the mixture was cooled to 0° C. After adding in dropwise to thismixture the solution which was prepared by adding 0.20 g of water to0.19 g (4.84 mmol) of sodium hydroxide, and then adding the solution inwhich 0.093 g (1.33 mmol) of hydroxylamine hydrochloride was dissolvedinto 0.48 g of water in dropwise, the mixture was reacted for 2 hours.The aqueous solution which was prepared from 0.76 g (7.26 mmol) of 35%hydrochloric acid and 2.27 g of water was added in dropwise to thereaction solution, and the mixture was stirred for 1 hour. Separationoperation was performed by adding 10 ml of ethyl acetate, and the ethylacetate was washed twice with 5 ml of water. The solvent was distilledoff under reduced pressure to obtain 0.49 g of3-(4-(1H-1,2,4-triazol-1-yl)phenyl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole(yield 94.7%).

Melting point 179 to 181° C.

Example 4-13 Synthesis of1-(4-(1H-imidazol-1-yl)phenyl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole

2.00 g of toluene and 1.22 g of N-methyl-2-pyrrolidone was added to 0.41g (0.99 mmol) of3-(4-(1H-imidazol-1-yl)phenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one,and the mixture was cooled to 0° C. After adding in dropwise to thismixture the solution which was prepared by adding 0.39 g of water to0.16 g (3.94 mmol) of sodium hydroxide, and then adding the solution inwhich 0.075 g (1.08 mmol) of hydroxylamine hydrochloride was dissolvedinto 0.16 g of water in dropwise, the mixture was reacted for 3 hours at0° C. The aqueous solution which was prepared from 0.62 g (5.91 mmol) of35% hydrochloric acid and 1.85 g of water was added in dropwise to thereaction solution, and the mixture was stirred for 1 hour. Separationoperation was performed by adding 30 ml of ethyl acetate, and the ethylacetate phase was washed twice with 20 ml of water. The solvent wasdistilled off under reduced pressure to obtain 0.41 g of3-(4-(1H-imidazol-1-yl)phenyl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole(yield 97.6%).

Melting point 193 to 195° C.

Example 4-14 Synthesis of5-(3,5-dichlorophenyl)-3-(4-(methylthio)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole

0.55 g of toluene and 0.33 g of N-methyl-2-pyrrolidone were added to0.11 g (0.28 mmol) of3-(3,5-dichlorophenyl)-4,4,4-trifluoro-1-(4-(methylthio)phenyl)-2-buten-1-one,and the mixture was cooled to 0° C. After adding in dropwise to thismixture the solution which was prepared by adding 0.11 g of water to0.045 g (1.12 mmol) of sodium hydroxide, and then adding the solution inwhich 0.022 g (0.31 mmol) of hydroxylamine hydrochloride was dissolvedinto 0.046 g of water in dropwise, the mixture was stirred for one nightat room temperature. The reaction was traced by high-performance liquidchromatography. Since the raw materials did not disappear, the solutionin which 0.018 g (0.25 mmol) of hydroxylamine hydrochloride wasdissolved into 0.038 g of water was added and stirred for 1 hour at roomtemperature. The aqueous solution which was prepared from 0.18 g (1.69mmol) of 35% hydrochloric acid and 0.53 g of water was added in dropwiseto the reaction solution, and the mixture was stirred for 1 hour. 5 mlof toluene was added and separation operation was performed. The toluenephase was washed twice with 3 ml of water. The solvent was distilled offunder reduced pressure to obtain 0.093 g of5-(3,5-dichlorophenyl)-3-(4-(methylthio)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole(yield 81.3%).

Melting point 114 to 116° C.

Example 4-15 Synthesis of3-(6-bromopyridin-3-yl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole

1.00 g of toluene and 0.60 g of N-methyl-2-pyrrolidone was added to 0.20g (0.47 mmol) of1-(6-bromopyridin-3-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one,and the mixture was cooled to 0° C. After adding in dropwise to thismixture the solution which was prepared by adding 0.19 g of water to0.075 g (1.88 mmol) of sodium hydroxide, and then adding the solution inwhich 0.036 g (0.52 mmol) of hydroxylamine hydrochloride was dissolvedinto 0.077 g of water in dropwise, the mixture was stirred for 2 hoursat 0° C. The aqueous solution which was prepared from 0.30 g (2.83 mmol)of 35% hydrochloric acid and 0.88 g of water was added in dropwise tothe reaction solution, and the mixture was stirred for 1 hour. 5 ml oftoluene was added to the reaction solution and separation operation wasperformed. The toluene phase was washed twice with 3 ml of water. Thesolvent was distilled off under reduced pressure to obtain 0.18 g of3-(6-bromopyridin-3-yl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole(yield 86.8%).

Melting point 147 to 148° C.

Example 4-16 Synthesis of3-(6-(1H-1,2,4-triazol-1-yl)pyridin-3-yl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole

2.50 g of toluene and 1.50 g of N-methyl-2-pyrrolidone were added to0.50 g (1.21 mmol) of1-(6-(1H-1,2,4-triazol-1-yl)pyridin-3-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one,and the mixture was cooled to 0° C. After adding in dropwise to thismixture the solution which was prepared by adding 0.49 g of water to0.20 g (4.92 mmol) of sodium hydroxide, and then adding the solution inwhich 0.094 g (1.35 mmol) of hydroxylamine hydrochloride was dissolvedinto 0.20 g of water in dropwise, the mixture was stirred for 2 hours at0° C. The aqueous solution which was prepared from 0.77 g (7.38 mmol) of35% hydrochloric acid and 2.31 g of water was added in dropwise to thereaction solution, and the mixture was stirred for 1 hour. The reactionsolution was cooled to room temperature, and separated by adding 20 mlof ethyl acetate and the ethyl acetate phase was washed twice with 10 mlof water. The solvent was distilled off under reduced pressure to obtain0.45 g of3-(6-(1H-1,2,4-triazol-1-yl)pyridin-3-yl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole(yield 87.3%).

Melting point 170 to 172° C.

Example 4-17 Synthesis of5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-(1H-1,2,4-triazol-1-yl)benzonitrile

1.52 g of toluene and 0.91 g of N-methyl-2-pyrrolidone were added to0.30 g (0.96 mmol) of5-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-(1H-1,2,4-triazol-1-yl)benzonitrile, and the mixture was cooled to 0° C. After adding indropwise to this mixture the aqueous solution which was prepared byadding 0.28 g of water to 0.11 g (2.77 mmol) of sodium hydroxide, andthen adding the solution in which 0.053 g (0.76 mmol) of hydroxylaminehydrochloride was dissolved into 0.11 g of water in dropwise, themixture was stirred for 2 hours at 0° C. The aqueous solution which wasprepared from 0.43 g (4.16 mmol) of 35% hydrochloric acid and 1.30 g ofwater was added in dropwise to the reaction solution, and the mixturewas stirred for 1 hour. 5 ml of toluene was added and separationoperation was performed. The toluene phase was washed twice with 3 ml ofwater. The solvent was distilled off under reduced pressure to obtain0.30 g of5-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-(1H-1,2,4-triazol-1-yl)benzonitrile (yield 94.5%).

¹H-NMR (CDCl₃, Me₄Si, 300 MHz) δ 8.89 (s, 1H), 8.22 (s, 1H), 8.10 (d,J=8.4 Hz, 2H), 7.93 (d, J=8.4 Hz, 1H), 7.51 (bs, 2H), 7.46 (d, J=1.7 Hz,1H), 4.12 (d, J=17.4 Hz, 1H), 3.76 (d, J=17.4 Hz, 1H).

Example 4-18 Synthesis of5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-fluorobenzonitrile

2.50 g of toluene and 1.50 g of N-methyl-2-pyrrolidone were added to0.50 g (1.29 mmol) of5-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-fluorobenzonitrile,and the mixture was cooled to 0° C. After adding in dropwise to thismixture the solution which was prepared by adding 0.52 g of water to0.21 g (5.16 mmol) of sodium hydroxide, and then adding the solution inwhich 0.099 g (1.42 mmol) of hydroxylamine hydrochloride was dissolvedinto 0.21 g of water in dropwise, the mixture was stirred for 2 hours at0° C. The aqueous solution which was prepared from 0.81 g (7.74 mmol) of35% hydrochloric acid and 2.42 g of water was added in dropwise to thereaction solution, and the mixture was stirred for 1 hour. 10 ml oftoluene was added and separation operation was performed. The toluenephase was washed twice with 5 ml of water. The solvent was distilled offunder reduced pressure to obtain 0.48 g of5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-fluorobenzonitrile(yield 92.9%).

Melting point 136 to 139° C.

INDUSTRIAL APPLICABILITY

The methods for producing according to the present invention are usefulproduction methods for isoxazoline compounds and intermediates thereofuseful for production intermediates for agricultural chemicals, medicaldrugs and functional materials.

The invention claimed is:
 1. A method for producing a1,3-bis(substituted phenyl)-3-substituted-3-hydroxypropan-1-one compoundrepresented by Formula (3):

wherein R¹ represents a trifluoromethyl group; each of A¹, A², A³ and A⁴independently represents C—Y; A⁶ represents C—H each of A⁵ and A⁷independently represents C—X; X represents a halogen atom or a C₁-C₆haloalkyl, and each X is optionally the same as or different from eachother; R² represents a halogen atom, cyano, —C(O)OH, —C(O)OR³, —C(O)NH₂,—C(O)N(R^(1b))R^(1a), or a substituent selected from D-21 to D-36; R³represents a C₁-C₆ alkyl, C₁-C₄ alkoxy (C₁-C₄) alkyl, or C₁-C₆haloalkyl; Y represents a hydrogen atom, cyano, or C₁-C₄ alkyl, and eachY is optionally the same as or different from each other; two adjacentYs optionally form A⁸=A⁹−A¹⁰=A¹¹ together; each of A⁸, A⁹, A¹⁰ and A¹¹independently represents C—Y¹; Y¹ represents a hydrogen atom; R^(1a)represents a C₁-C₆ alkyl optionally substituted by R⁸, —N(R¹¹)R¹⁰,—C(O)OR⁹, —C(O)NH₂, —C(O)NHR⁹, —C(R⁷)═NOR⁶, phenyl, phenyl substitutedby (Z)_(p1), D-5, D-7, D-10, D-11, D-12, D-14, D-15, D-18, D-31, D-32,D-42, D-43, D-45, D-46, D-48, E-1, or E-7; R^(1b) represents a hydrogenatom, C₁-C₆ alkyl, C₁-C₄ alkoxy (C₁-C₄) alkyl, cyano (C₁-C₆) alkyl,C₃-C₆ alkynyl, —C(O)R⁹ or —C(O)OR⁹, or represents that R^(1b) optionallyforms a 3-7 membered ring with a nitrogen atom to be bonded, by forminga C₂-C₆ alkylene chain together with R^(1a), and this alkylene chainoptionally contains one oxygen atom, sulfur atom or nitrogen atom inthis case; R⁶ represents a C₁-C₆ alkyl; R⁷ represents a hydrogen atom orC₁-C₆ alkyl; R⁸ represents a halogen atom, cyano, C₃-C₆ cycloalkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkoxy —C(O)N(R¹⁵)R¹⁴, —C(R⁷)═NOR⁶, phenyl,phenyl substituted by (Z)_(p1), D-11 to D-14, D-18, D-19, D-25, D-26,D-31, D-32, D-36, D-42, D-45, D-48, D-49, E-1, E-2, or E-5; D-3 to D-5,D-7, D-9 to D-15, D-18 to D-36, and D-42 to D-49 represent aromaticheterocyclic rings represented by the following structural formulae:

Z represents a halogen atom, cyano, nitro, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ haloalkoxy, and each Z is optionally the same as or different fromeach other when p1, p2, p3 or p4 represents an integer of 2 or more;E-1, E-2, E-5, and E-7 represent saturated heterocycles represented bythe following structural formulae:

R⁹ represents a C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy (C₁-C₄)alkyl, C₁-C₆ alkylthio (C₁-C₄) alkyl, C₃-C₈ cycloalkyl, C₃-C₆ alkenyl orC₃-C₆ alkynyl; R¹⁰ represents a C₁-C₆ haloalkyl, —C(O)R¹⁴, —C(O)OR¹⁴,phenyl, phenyl substituted by (Z)_(p1), D-3, D-4, D-18, D-42, D-45,D-46, D-48 or D-49; R¹¹ represents a hydrogen atom, C₁-C₆ alkyl or C₃-C₆alkynyl; R¹² represents a C₁-C₆ alkyl; R¹³ represents a C₁-C₄ alkyl, andeach R¹³ is optionally the same as or different from each other when q2,q3 or q4 represents an integer of 2 or more, wherein two R¹³s optionallyform oxo together when two R¹³s are bonded to the same carbon atom; R¹⁴represents a C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl (C₁-C₄)alkyl, C₃-C₆ cycloalkyl, C₃-C₆ alkenyl or C₃-C₆ alkynyl; R¹⁵ representsa hydrogen atom or C₁-C₆ alkyl; R¹⁶ represents a —OH, C₁-C₄ alkoxy orC₁-C₄ alkylthio; R¹⁷ represents a hydrogen atom, C₁-C₆ alkyl, C₃-C₆cycloalkyl, C₃-C₆ alkenyl, C₃-C₆ haloalkenyl, C₃-C₆ alkynyl,—C(R⁵)═NOR¹⁹, —C(O)OR¹⁹, —C(O)NH₂, —C(O)N(R⁵)R¹⁹, —C(O)NHC(O)R¹⁹,—C(O)N(R⁵)C(O)OR¹⁹, —N(R²¹)R²⁰, phenyl substituted by (Z)_(p1), D-9 toD-11, D-18 to D-20, D-42 to D-47 or D-48; R¹⁸ represents a hydrogenatom, C₁-C₆ alkyl, C₃-C₆ alkynyl, —C(O)R^(19a), —C(O)OR^(19a) or C₁-C₆haloalkylthio; R¹⁹ represents a C₁-C₆ alkyl, C₁-C₆ haloalkyl or C₂-C₆alkenyl; R^(19a) represents a C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₄ alkoxy(C₁-C₄) alkyl, C₁-C₄ alkylthio (C₁-C₄) alkyl, C₁-C₄ alkylsulfinyl(C₁-C₄) alkyl, C₁-C₄ alkylsulfonyl (C₁-C₄) alkyl, C₃-C₆ cycloalkyl,C₂-C₆ alkenyl, C₁-C₆ alkoxycarbonyl, phenyl, phenyl substituted by(Z)_(p1), D42, D43 or D44; R²⁰ represents a C₁-C₆ haloalkyl, C₁-C₆alkoxycarbonyl, phenyl, phenyl substituted by (Z)_(p1), D42 to D46 orD47; R²¹ represents a hydrogen atom, C₁-C₆ alkyl, C₃-C₆ alkenyl or C₃-C₆alkynyl; p1 represents an integer of 1 to 2; p2 represents an integer of0 to 1; p3 represents an integer of 0 to 1; p4 represents an integer of0 to 1; p5 represents an integer of 0 or 1; q2 represents an integer of0 to 2; q3 represents an integer of 0 to 2; q4 represents an integer of0 to 2; r represents an integer of 0 to 2; t represents an integer of 0or 1, the method consisting of reacting an aromatic ketone compoundrepresented by Formula (4)

wherein R¹, A⁵, A⁶ and A⁷ represent the same meaning as described above,and a substituted acetophenone compound represented by Formula (5)

wherein R², A¹, A², A³ and A⁴ represent the same meaning as describedabove, in a suspended state in the presence or absence of an additiveand in the presence of a base in a solvent, wherein the base is selectedfrom the group consisting of sodium acetate, potassium acetate,methylamine, ethylamine, n-propylamine, i-propylamine, n-butylamine,i-butylamine, t-butylamine, n-pentylamine, i-pentylamine, benzylamine,aniline, dimethylamine, diethylamine, di-n-propylamine,di-i-propylamine, di-n-butylamine, di-i-butylamine, di-n-pentylamine,di-i-pentylamine, pyrrolidine, piperidine, piperazine, morpholine,dibenzylamine, trimethylamine, triethylamine, tri-n-propylamine,tri-n-butylamine, tripentylamine, tribenzylamine, diisopropylethylamine,N-methylmorpholine, and combinations thereof, and the additive isselected from the group consisting of a C₁-C₆ alcohol, an aprotic polarsolvent, a surfactant, a water soluble organic solvent, and combinationsthereof.
 2. The method according to claim 1, wherein the solvent is anorganic solvent and the reaction is conducted in the absence of theadditive.
 3. The method according to claim 1, wherein the solvent iswater and the reaction is conducted in the presence of a water-solubleorganic solvent as the additive.
 4. The method according to claim 1,wherein the solvent is water and the reaction is conducted in thepresence of a surfactant as the additive.
 5. The method according toclaim 1, wherein R² represents a halogen atom, —C(O)OH, —C(O)OR³,—C(O)NH₂, —C(O)N(R^(1b))R^(1a), or a substituent selected from D-21 andD-36.
 6. The method according to claim 5, wherein R^(1a) represents aC₁-C₆ alkyl optionally substituted by R⁸—N(R¹¹)R¹⁰, —C(O)OR⁹, —C(O)NH₂,—C(O)NHR⁹, or —C(R⁷)═NOR⁶; and R^(1b) represents a hydrogen atom, C₁-C₆alkyl, C₁-C₄ alkoxy (C₁-C₄) alkyl, cyano (C₁-C₆) alkyl, C₃-C₆ alkynyl,—C(O)R⁹ or —C(O)OR⁹.
 7. The method according to claim 6, wherein R^(1a)represents a C₁-C₆ alkyl optionally substituted by R⁸; and R^(1b)represents a hydrogen atom, C₁-C₆ alkyl, C₁-C₄ alkoxy (C₁-C₄) alkyl,cyano (C₁-C₆) alkyl, C₃-C₆ alkynyl.
 8. The method according to claim 7,wherein R^(1b) represents a hydrogen atom; R³ represents a C₁-C₆ alkyl;and when present, R⁸ represents D-42.
 9. The method according to claim8, wherein Y represents a hydrogen atom, cyano, or C₁-C₄ alkyl, and eachY is optionally the same as or different from each other.
 10. The methodaccording to claim 1, wherein the base is selected from the groupconsisting of diethylamine, di-i-propylamine, di-n-propylamine,di-n-butylamine, pyrrolidine, triethylamine, tri-n-butylamine, andcombinations thereof.
 11. The method according to claim 1, wherein thebase is selected from the group consisting of methylamine, ethylamine,n-propylamine, i-propylamine, n-butylamine, i-butylamine, t-butylamine,n-pentylamine, i-pentylamine, and combinations thereof.